The  Dandridge  Volume 


Being  a  series  of  papers  presented  at 
various  times  in  the  meetings  of  the 
CINCINNATI  RESEARCH  SOCIETY 
and  dedicated  by  it  to  the  memory  of 
its  distinguished  member 

Nathaniel  Pendleton  Dandridge,  M.D. 


^^^^^  ^ 


p^ 


Cincinnati,  Ohio 
1913 


THE  LANCET-CLINIC  PRESS 

CINCIXXATI 


library 


:Biodrapby 


NATHANIEL  PENDLETON  DANDRIDGE  was  born  in 
Cincinnati,  O.,  on  the  16th  of  April,  1846.  His  parents  were 
Dr.  Alexander  Spots woode  Dandridge,  a  physician  of  high  pro- 
fessional and  social  standing  in  his  day,  and  Martha  Eliza  Pen- 
dleton. Both  the  Dandridge  and  the  Pendleton  families  were 
among  the  early  settlers  of  Virginia,  of  English  and  Scotch 
stock,  and  are  identified  in  many  ways  with  the  most  important 
events  in  its  history. 

■  Dr.  Nathaniel  Pendleton  Dandridge  received  his  elementary 
education  in  a  private  school  in  Cincinnati,  and  later  entered 
Kenyon  College,  Gambler,  O.,  from  which  he  was  graduated  with 
the  class  of  1866.  The  scholastic  year  of  1866-67  was  spent  as 
a  student  in  the  jMedical  College  of  Ohio.  In  the  summer  of  1867 
he  went  abroad,  where  he  studied  medicine  in  Paris  in  1867-68 
and  in  Vienna  in  1868-69.  At  that  time  these  were  the  most 
famous  medical  schools  in  the  world.  Returning  to  the  United 
States  with  what  was  at  that  period  much  more  than  an  ordinary 
medical  education.  Dr.  Dandridge  entered  the  College  of  Physi- 
cians and  Surgeons  of  New  York,  and,  after  taking  the  winter 
course  of  1869-70,  received  his  degree  of  Doctor  of  INIedicine 
from  that  institution. 

Returning  to  his  home  in  Cincinnati,  in  1872,  he  was  appointed 
pathologist  to  the  Cincinnati  Hospital,  a  position  which  he  held 
for  eight  years,  during  which  time  he  taught  pathology  as  he  had 
learned  it  from  the  lips  of  the  great  masters  in  Paris  and  Vienna, 
and  enriched  the  museum  of  the  hospital  with  many  specimens 
intelligently  and  carefully  prepared  by  his  own  hands.  This 
appointment,  coming  so  soon  after  his  pathological  and  clinical 
studies  abroad,  laid  a  sure  and  broad  foundation  for  that  remark- 
ably comprehensive  knowledge  of  general  surgery  which  later 
brought  the  profound  admiration  and  respect  of  his  colleagues 
and  the  profession  at  large. 

5 


HN 


2^07259 


6  DANDRIDGE  MEMORIAL 

In  1880  he  was  appointed  surgeon  to  the  Cincinnati  Hospital, 
and  in  the  same  year  was  made  professor  of  surgery  in  the  Miami 
Medical  College  (recently  merged  with  the  Medical  College  of 
Ohio  to  form  the  Medical  Department  of  the  University  of  Cin- 
cinnati). It  is  as  the  incumbent  of  these  two  positions  that  he 
will  be  most  vividly  remembered  by  his  juniors  in  the  medical 
profession  of  Cincinnati  and  the  surrounding  States.  His  lectures 
were  clear,  concise,  illuminated  by  the  sound  common  sense  that 
characterized  his  argument,  and,  when  the  occasion  permitted  it, 
enlivened  by  a  glow  of  that  genial  humor  which  always  rose 
spontaneously  from  his  heart  to  his  lips. 

In  1887  he  was  appointed  to  the  Board  of  Examiners  of  the 
recently  reorganized  Police  Department.  This  position  he  held 
until  1896,  when  he  resigned.  It  was  during  this  period  that  the 
present  high  standard  of  physical  development  of  the  members 
of  the  police  force  was  set. 

Although  Dr.  Dandridge's  position  as  surgeon  to  the  Cincin- 
nati Hospital  brought  him,  justly,  a  wide  fame  and  membership 
in  many  learned  societies,  such  as  the  Southern  Surgical  and 
Gynecological  Association,  the  American  Surgical  Association  and 
the  Academy  of  Surgeons  of  Philadelphia,  it  is  probable  that  the 
professional  appointment  in  which  he  took  the  keenest  pleasure, 
and  to  which  he  unselfishly  devoted  the  greatest  amount  of  time 
and  eftort,  was  his  service  at  the  Episcopal  Free  Hospital  for 
Children.  His  gentle  and  kindly  disposition  was  seen  at  its  best 
in  the  wards  of  this  most  excellent  charity,  to  which  he  was  one 
of  the  surgeons  for  many  years.  Although  no  lectures  to  students 
were  conducted  in  this  institution,  surgical  literature  was  enriched 
by  Dr.  Dandridge  by  many  papers  on  the  surgical  diseases  of  the 
bones  and  joints,  the  necessary  observations  for  which  were 
acquired  in  the  wards  and  operating  room  of  this  hospital. 

In  1909  he  resigned  his  position  as  surgeon  to  the  Cincinnati 
Hospital,  and  accepted  an  appointment  on  the  Board  of  Medical 
Directors  of  that  institution.  Twenty-five  years  previously  hi-5 
father  had  been  a  m.ember  of  the  governing  body  of  the  hospital, 
having  served  on  the  Board  of  Trustees  for  a  number  of  years. 

In  addition  to  the  professional  appointments  and  honors  al- 


BIOGRAPHY  7 

ready  recorded,  Dr.  Dandridge  was  at  the  time  of  his  death,  in 
1910,  a  member  of  the  Cincinnati  Academy  of  Aledicine,  the  Ohio 
State  Medical  Society,  the  American  jMedical  Association,  the 
Southern  Surgical  and  Gynecological  Association,  and  an  Hon- 
orary Fellow  of  the  Academy  of  Surgery  of  Philadelphia. 

He  was  also  a  trustee  of  Kenyon  College,  and,  by  right  of 
descent,  a  member  of  the  Sons  of  the  Revolution  and  the  Virginia 
Chapter  of  the  Society  of  Colonial  Wars. 

Christian  R.  Holmes. 


(Contents 


PAGE 

Biography   5 

S.  P.  Kramer,  ]\I.D. 

The  Pathogenesis  of  Gail-Stones 13 

Paul  G.  Woolley,  B.S.,  M.D.,  and  L.  H.  Xewburgh,  A.B.,  M.D. 

Aortic  Aneurism  with  Rupture  into  the  Pulmonary  Artery 19 

Creighton  Wellman,  M.D.,  and  Wm.  B.  Wherry,  A.B.,  M.D. 

Some  New  Internal  Parasites  of  the  California  Ground  Squirrel 

(Otospermophilus  Beecheyi)    27 

Sidney  Lange,  B.S.,  M.D. 

The  Pathology  of  Mastoiditis  as  Revealed  by  the  X-Ray 33 

Otto  V.  Huffman,  M.D. 

Miners'    Consumption    43 

Oscar  Berghausen,  A.B.,  M.D. 

The    Wassermann    Reaction 47 

Oscar  Berghausen,  A.B.,  M.D. 

The  Significance  of  Ehrlich's  Aldehyde  Reaction  in  the  Urine....     55 
Otto  V.  Huffman,  M.D. 

Impetigo  Contagiosa  Transmitted  by  Machine  Oil 67 

Albert  H.  Freiberg,  M.D.,  and  Paul  G.  Woolley,  B.S.,  M.D. 

Osteochondritis  Dissecans :  Concerning  its  Nature  and  Relation  to 

Formation  of  Joint  Mice 69 

Otto  V.  Huffman,  M.D.,  and  Wm.  B.  Wherry,  A.B.,  M.D. 

A  Description  of  Four  Filaria  Loa  from  the  Same  Patient 81 

Otto  V.  Huffman,  M.D. 

The   Embryos   of  Filaria   Loa 91 

William  Ravine,  M.D. 

The  Successful  Treatment  of  a  Case  of  Illuminating  Gas  Poison.     99 
J.  L.  Tuechter,  M.D. 

Unequal  Pupils  as  an  Early  Sign  in  Phthisis 105 

Paul  G.  Woolley,  B.S.,  M.D. 

Acute    Tuberculous    Endaortitis 109 

S.  P.  Kramer,  M.D. 

The  Function  of  the  Choroid  Plexuses  of  the  Cerebral  Ventricles 

and  its  Relation  to  that  of  the  Pituitary  Gland 115 

9 


10  DANDRIDGE    MEMORIAL 

PAGE 

Paul  G.  Woolley,  B.S.,  M.D.,  and  L.  H.  Newburgh,  A.B.,  M.D. 

The  Effect  of  Injections  of  Indol  and  Tyrosin  in  Experimental 
Animals   119 

Paul  G.  Woolley,  B.S.,  M.D. 

Amyloid  Degeneration  Localized  in  the  Adrenal 123 

Arthur  D.  Dunn,  A.B.,  M.D.,  and  Paul  G.  Woolley,  B.S.,  M.D. 

Acquired  Diverticula  of  the  Sigmoid  with  a  Report  of  Six  Cases. .   127 

William  H.  Peters,  M.D. 

A  Simple  Method  of  Cultivating  the  Morax-Axenfeld  Diplobacillus  145 

John  E.  Greiwe,  M.D. 

The    Electrocardiogram    147 

Paul  G.  Woolley,  B.S.,  M.D.,  and  Otto  V.  Huffman,  M.D. 

The  Ova  of  Schistosoma  Japonicum  and  the  Absence  of  Spines..   161 

M.  L.  Heidingsfeld,  M.D. 

Hairy   or   Black   Tongue 163 

William  H.  Peters,  M.D. 

Hand  Infection  Apparently  Due  to  Bacillus  Fusiformis 177 

Otto  V.  Huffman,  M.D. 

The  Kurloff-Body,  a  Spurious  Parasite 185 

Alfred  Friedlander,  A.B.,  M.D. 

Involution  of  the  Thymus  by  the  X-Ray 191 

Oscar  Berghausen,  A.B.,  M.D. 

The  Role  of  Acidosis  of  the  Tissue  as  a  Factor  in  the  Production 

of  an  Attack  in  Paroxysmal  Hemoglobinuria 207 

L.  H.  Newburgh,  A.B.,  M.D.,  and  Paul  G.  Woolley,  B.S.,  M.D. 

The  Effects  Produced  by  Numerous  Injections  of  Indol  and  Tyro- 
sin in  Experimental  Animals :  A  Contribution  to  the  Study 
of   Chronic  Intestinal   Indications 215 

Martin  H.  Fischer,  M.D. 

Contributions  to  a  Colloid-Chemical  Analysis  of  Absorption  and 
Secretion     225 

Henry  Louis  Wieman,  Ph.D. 

The  Relation  between  Cyto-Reticulum  and  the  Fibril  Bundles  in 

the  Heart  Muscle  Cell  of  the  Chick 263 

Charles  Goosmann,  M.D. 

A  Method  of  Demonstrating   Spirochstae  and  Tr3'panosomes  by 

Means    of    Nigrosin 277 


CONTENTS  11 

William  H.  Strietmann,  A.B.,  ^\i.D.,  and  Martin  H.  Fischer,  M.D. 
On  the  Contraction  of  Catgut  and  the  Theory  of  Muscular  Con- 
traction      283 

Paul  G.  Woolley,  B,S.,  M.D.,  and  Herbert  A.  Brown,  M.D. 

An  Anomalous  Duct  Belonging  to  the  Urinary  Tract 303 

Eugene  S.  May,  M.D. 

The  Germicidal  Action  of  Basic  Fuchsin 307 

Paul  G.  Woolley,  B.S.,  MD.,  and  Wm.  B.  Wherry,  A.B.,  M.D. 

Notes   on   Twenty-two   Spontaneous  Tumors   in  Wild  Rats    (M. 
Norvegicus)     313 

A.  E.  Osmond,  M.D. 

A  Computing  Chart  for  Making  a  Differential  Leucocyte  Count..  325 

The   Cincinnati   Research   Society 328 


THE  PATHOGENESIS  OF  GALL-STONES. 


BY  S.   P.    KRAMER^   M.D. 


The  ultimate  cause  for  the  formation  of  gall-stones  has,  not- 
withstanding the  large  amount  of  investigation  on  the  subject, 
remained  a  subject  for  speculation. 

The  earliest  view  was  a  purely  mechanical  one ;  that  the 
formation  of  the  stones  was  the  result  of  concentration  due  to 
stagnation.  On  account  of  the  fact  that  bile  may  be  concentrated 
to  a  thick  mass  without  the  precipitation  of  the  products  found 
in  gall-stones,  this  view  had  to  be  abandoned. 

There  then  followed  the  so-called  chemical  theory,  the  chief 
exponent  of  which  was  Thudichum.^  Cholestearin,  bilirubin  and 
the  calcium  salts  are  soluble  in  alkaline  solution,  especially  in 
solutions  of  sodium  glycocholate,  and  concentration  does  not 
bring  about  precipitation,  li,  however,  according  to  Thudichum, 
as  the  result  of  decomposition  due  to  prolonged  standing  or  as 
the  result  of  abnormal  secretion  of  mucus,  the  bile  becomes  acid, 
the  cholestearin  and  bilirubin  calcium  are  precipitated  as  the  re- 
sult of  the  decomposition  of  the  solvent,  sodium  glycocholate, 
into  glycocoll,  cholaic  acid  and  a  sodium  salt.  In  reading  the 
work  of  Thudichum,  it  is  well  to  remember  that  the  work  was 
done  a  half  century  ago,  and,  of  course,  without  bacterial  investi- 
gation. 

Another  chemical  explanation  was  offered  by  Dochmann-  in 
1891.  He  analyzed  both  liver  and  bladder  bile,  the  latter  ob- 
tained after  ligation  of  the  cystic  duct,  and  found  a  great  increase 
in  calcium  and  diminution  in  sodium  in  bladder  bile  as  compared 
with  liver  bile.  According  to  his  view  the  increase  in  calcium 
diminishes  the  solubility  of  bilirubin  and  leads  to  a  precipitation 
'"f  bilirubin  calcium  and  cholestearin.  Prolonged  intervals  be- 
tween meals  and  stasis  cause  a  stagnation  and  precipitation  of 
bilirubin  calcium  and  cholestearin. 

*    Reprinted  from  the  Journal  of  Experimental  Medicine,  May,  1907, 

13 


14  DANDRIDGE    MEMORIAL 

Opposed  to  these  chemical  theories  are  the  morphological  and 
bacteriological  theories.  Dujardin  Beaumetz'  ascribes  the  forma- 
tion of  gall-stones  to  a  desquamative  cholangitis  and  biliary  stasis, 
thus  reviving  the  "Steinbildende  Katarrh"  of  Meckel.* 

Naunyn^  denies  the  chemical  theory  of  Thudichum.  Even 
when  greatly  concentrated,  bile  contains  sufficient  solvent  to  keep 
the  cholestearin  and  bilirubin  calcium  in  solution.  The  decompo- 
sition of  sodium  glycocholate  to  sodium  cholate  does  not  explain 
the  precipitation,  since  this  product  is  also  a  solvent  for  chole- 
stearin and  bilirubin  calcium.  He  also  ascribes  the  formation  of 
gall-stones  to  a  desquamative  cholangitis. 

This  inflammatory  process  leads  to  a  desquamation  of  epithelial 
cells  which  degenerate  and  form  cholestearin  and  calcium  salts. 
The  bilirubin  unites  with  the  calcium.  The  precipitation  of  bili- 
rubin calcium  is  aided  by  the  albuminous  character  of  the  products 
of  cellular  degeneration,  alluding  here  to  the  general  tendency  of 
albumen  to  precipitate  calcium. 

In  this  way  are  formed  small  particles  which  form  the  nuclei 
of  gall-stones.  The  cholestearin  is  deposited  later,  partly  on  the 
outside  and  partly  infiltrating  the  mass  through  the  so-called  in- 
filtration canals  which  are  found  in  gall-stones.  The  mere  excess 
of  calcium  will  not  cause  a  precipitation  of  bilirubin  in  calcium 
and  cholestearin.  Even  the  presence  of  foreign  bodies  as  centers 
of  crystallization  will  not  bring  this  about. 

There  is  lacking  the  explanation  of  some  biological  process 
which  brings  this  about,  and  this,  according  to  Naunyn,  is  fur- 
nished by  the  degeneration  of  epithelial  cells  the  result  of  an 
infective  cholangitis. 

We  have  still,  however,  no  explanation  as  to  the  process  by 
which  cholestearin  and  calcium  salts,  which  are  normally  soluble 
in  bile,  are  precipitated  in  cholelithiasis.  To  say  that  it  is  the 
result  of  degenerative  changes  in  epithelium,  produces  more 
mystery,  but  no  explanation. 

If  now  we  leave  the  realm  of  speculation  and  search  for  some 
exact  knowledge,  a  very  curious  chain  of  thought  will  arise.  We 
have,  heretofore,  exact  knowledge  of  the  formation  of  stones  in 
one  instance  and  in  one  only.  I  refer  to  the  formation  of  phos- 
phatic  urinary  calculi.    We  know  that  this  is  due  to  chemical  de- 


KRAMER  15 

composition,  the  direct  result  of  bacterial  growth.  If  now  we 
apply  this  knowledge  to  experiments,  having  for  their  object  the 
clearing  up  of  the  subject  of  gall-stones,  it  may  be  that  some  suc- 
cess will  follow.  It  has  been  abundantly  proven,  that  bacteria  are 
at  all  times  present  in  gall-stones.  The  literature  on  the  subject  is 
so  well  known  that  it  is  not  necessary  to  burden  this  article  with  it. 

The  colon  bacillus  is  the  organism  most  frequently  found  in 
gall-stones.  The  one  next  in  frequency  is  the  typhoid  bacillus. 
It  is  very  probable  that  it  will  be  found  that  infection  by  one  of 
these  two  micro-organisms  is  responsible  for  most  cases  of  chole- 
lithiasis. 

Now  while  this  has  been  commonly  accepted,  it  seems  strange 
that  there  should  be  no  investigation  published,  showing  the  effect 
of  these  organisms  on  bile  when  grown  in  it. 

It  would  appear  a  priori  reasonable,  that  possibly  the  growth 
of  these  organisms  in  bile,  or  a  solution  of  bile,  would  effect  the 
precipitation  of  some  of  the  biliary  constituents.  Accordingly,  for 
the  past  year,  I  have  been  carrying  out  such  an  investigation  with 
most  gratifying  results. 

Culture  tubes  were  prepared  containing  a  mixture  of  one  half 
human  bile  obtained  at  autopsy  and  one  half  ordinary  alkaline 
pepton  bouillon.  This  mixture  or  solution  was  repeatedly  ster- 
ilized and  filtered,  until  a  perfectly  clear  medium  was  obtained. 
Such  tubes  were  inoculated  with  the  colon  bacillus,  the  typhoid 
bacillus  and  staphylococcus  pyogenes  aureus.  All  of  these  micro- 
organisms grow  readily  in  this  medium.  The  staphylococcus 
forms  a  copious  growth  which  sinks  to  the  bottom  of  the  tube, 
the  medium  showing  no  apparent  change. 

Not  so,  however,  with  those  inoculated  with  the  colon  or  ty- 
phoid bacillus.  Here  in  a  few  days  the  medium  became  cloudy 
and  a  precipitate  is  seen  at  the  bottom  of  the  tube.  This  precipi- 
tate increases  greatly  until  in  about  four  weeks  a  very  well  marked, 
closely  packed,  semi-solid  mass  is  seen  at  the  bottom  of  the  tube. 
If  allowed  to  incubate  longer,  say  for  six  months,  care  being  taken 
to  prevent  evaporation  by  rubber  caps,  this  precipitated  mass  be- 
comes firmly  packed  and  the  super-natant  fluid  may  be  poured  off 
and  we  have  a  kind  of  very  soft  "gall-stone"  as  it  were,  taking  the 
form  of  the  bottom  of  the  tube.    If  we  examine  the  precipitate,  we 


16  DANDRIDGE    MEMORIAL 

have  no  difficulty  in  recognizing  all  the  constituents  of  gall-stones 
as  well  as  masses  of  bacilli:  Amorphous  calcium  phosphate,  mag- 
nesium phosphate,  calcium  carbonate,  biliary  coloring  matter  and 
a  few  crystals  of  cholestearin.  Crystals  of  ammonio-magnesium 
phosphate  are  formed  very  late,  usually  after  many  weeks  of 
growth. 

In  order  that  the  precipitation  of  cholestearin  might  be  made 
more  manifest,  and  since,  normally,  bile  contains  comparatively 
little  of  it,  culture  tubes  were  prepared  in  which  cholestearin  was 
added  to  the  solution  of  bile  and  bouillon.  This  readily  dissolves 
therein  and  the  medium  was  carefully  filtered  and  examined 
microscopically  before  inoculated,  so  as  to  be  sure  that  all  the 
cholestearin  present  was  in  solution.  Such  tubes  v;hen  inoculated 
with  colon  or  typhoid  bacillus,  give  a  precipitate  very  rich  in 
cholestearin  crystals. 

Another  thing  which  was  remarked,  was  the  markedly  pre- 
servative action  of  bile  upon  colon  and  typhoid  bacilli.  I  have  at 
present  tubes  in  which  the  precipitate  was  separated  and  allowed 
to  dry  out  completely,  and  yet  the  bacilli  present  are  still  viable 
and  readily  resume  growth  when  inoculated  upon  fresh  media. 
This  corresponds  with  the  findings  that  viable  typhoid  bacilli  have 
been  found  in  the  interior  of  gall-stones  years  after  the  individual 
had  passed  through  the  attack  of  typhoid  fever. 

Thus  Droba''  reports  a  case  in  which  he  obtained  the  typhoid 
bacillus  from  gall-stones  removed  seventeen  years  after  the  patient 
had  recovered  from  typhoid  fever. 

It  appears  to  me  that  these  experiments  indicate  very  clearly 
then  that  gall-stone  formation,  just  as  phosphatic  urinary  stone 
formation,  is  due  to  a  chemical  decomposition  of  the  bile,  the 
direct  result  of  the  growth  of  micro-organisms  therein.  Bacillus 
coli  communis  and  bacillus  typhosus  are  the  micro-organisms 
usually  concerned.  Just  what  the  exact  chemical  nature  of  the 
decomposition  is,  remains  to  be  shown.  It  is  rather  significant, 
however,  that  the  two  micro-organisms  which  cause  this  precipita- 
tion in  vitro,  produce  an  acid  reaction  in  the  media.  \\'hereas,  the 
staphylococcus,  which  requires  and  retains  in  alkaline  reaction, 
does  not  cause  the  precipitation. 

It  may  be  then  that  the  decomposition  theory  oi  Thudichum 


KRAMER  17 

will  prove  to  be  true  in  a  modified  form.  His  work  on  the  de- 
composition of  bile  was  done,  of  course,  before  the  days  of  pure 
culture,  and  was  without  bacterial  control.  A  repetition  of  his 
analyses  of  bile  decomposed  by  pure  culture  of  these  organisms 
may  give  us  the  exact  chemical  nature  of  the  process. 

REFERENCES. 

1.  Thudichum,  Quarterly  Journal  of  the  Chemical  Society,  1862,  xiv,  114. 

2.  Dochmann,  Wien.  med.  Presse,  1891,  xxxii,  1198. 

3.  Dujardin  Beaumetz,  Bui.  Thcrap.,  1891,  cxxi,  291. 

4.  Meckel  von  Helmsbach,  "Mikro-geologie,"  1856,  Berlin. 

5.  Naunyn,  "Klinik  der  Cholelithiasis,"   1892. 

6.  Droba,  Wien.  klin.  IVoch.,  1899,  xii,  1141. 


AORTIC  ANEURISAI  WITH  RUPTURE  INTO  THE  PUL- 
MONARY ARTERY. 


r.V  PAUL  G.   WOOLLEV,    M.I)., 
A.XO    I..     11.    NEWBURGII.    M.I). 


Perhaps  the  best  reason  which  can  be  given  for  a  new  review 
of  the  cases  of  aortic  aneurism  that  have  ruptured  into  the  pul- 
monary arter}^,  is,  that  in  spite  of  the  fact  that  some  forty-nine 
such  ca.ses  have  been  reported,  a  correct  diagnosis  has  been  made 
in  but  three,  A  subsidiary  reason  is  that  although  an  extensive 
study  of  the  cases  in  the  literature  has  been  made  by  Kappis.  there 
is  no  comprehensive  review  of  them  in  English. 

To  the  series  of  cases  already  reported  we  wish  to  add  another, 
the  history  of  which  is  as  follows  : 

Case  No.  152,041. — The  patient  was  a  colored  laboring  man, 
forty  years  old,  who  was  admitted  to  the  medical  service  of  the 
Cincinnati  Hospital  complaining  of  pain  in  the  left  side  and 
shortness  of  breath.     He  died  three  months  after  admission. 

The  patient  gave  a  history  of  the  usual  diseases  of  childhood, 
of  smallpox,   rheumatic   fever,  gonorrhea  and  syphilis. 

Shortness  of  breath  commenced  five  weeks  before  admission. 
The  symptoms  gradually  became  more  pronounced,  and  were 
associated   with   cough   and   night   sweats. 

On  admission  his  temperature  was  96.8°,  pulse  96  and  res- 
piration 32.  The  tho-rax  was  symmetrical.  The  respiration  was 
labored,  but  the  respiratory  movements  of  the  thorax  were  of 
normal  extent,  except  in  the  right  axillary  region,  where  they 
were  diminished.  The  percussion  note  was  flat  in  the  left  ax- 
illa. There  was  a  friction  rub  on  the  left  side,  and  in  this  region, 
low'  in  the  axilla,  the  breath  sounds  were  distinct. 

Tlie  outline  of  cardiac  dullness  was  increased  both  vertically 
and  transversely.  The  apex  beat  was  felt  in  the  sixth  intercostal 
space,  close  to  the  axillary  line ;  it  was  forcible,  strong  and  reg- 
ular, and  fairly  well  circumscribed.  At  the  apex  an  inconstant, 
soft,  systolic  bruit  of  varying  intensity  could  be  heard.  At  the 
level  of  the  junction  of  the  fourth  rib  and  at  the  sterno-costal 

19 


20  DANDRIDGE    MEMORIAL 

junction  a  rough,  svstolic  and  a  prolonged  and  somewhat  smooth 
diastolic  bruit  were  heard.  Both  of  these  varied  considerably  in 
physical  properties,  at  times  being  almost  inaudible  and  again 
loud.  The  aortic  diastolic  bruit  occasionally  disappeared.  Per- 
cussion showed  an  abnormal  area  of  dullness  above  the  base  of 
the  heart.  The  pulse  was  regular,  full,  large  and  strong — a 
typical  Corrigan. 

At  the  time  of  entrance  there  was  no  edema  of  legs.  Later  the 
patient  became  more  and  more  short  of  breath  to  the  extent  that 
sleeping  was  inter fered^  with.  Still  later  dyspnea  made  it  nec- 
essary to  assume  a  sitting  position  at  night,  and  vomiting  com- 
menced and  continued  intermittently. 

The  respiratory  symiptoms  gradually  increased  in  severity, 
the  systolic  murmurs  at  the  apex  became  quite  regular,  soft  and 
smooth.  To  the  right  of  the  nipple  a  rough  systolic  and  a  dias- 
tolic murmur  could  be  heard.  The  aortic  diastolic  murmurs  be- 
came less  intense,  and  a  pericardial  friction  developed.  The  legs 
became  more  and  more  edematous ;  the  edema  constantly  ex- 
tended toward  the  body,  and  gradually  the  patient  became  weaker, 
sank  and  died. 

At  no  time  was  sugar  or  albumin  present  in  the  urine,  though 
the  specific  gravity  reached  1,030. 

Clinical  Diagnosis. — Syphilitic  aortitis;  aortic  stenosis  and 
regurgitation;  passive  congestion  of  the  kidneys. 

The  autopsy  was  done  two  hours  after  death.  The  report 
is,  briefly,  as  follows :  The  body  was  that  of  a  poorly  nourished, 
middle-aged  negro.  The  lower  part  of  the  body,  from  the  um- 
bilicus down  was  enormously  swollen,  edematous,  and  presented 
numerous  large  and  small  blebs.  Post-morten  rigidity  slightly 
evident  in  feet ;  absent  elsewhere.  The  peripheral  lymph  glands 
were  not  enlarged.  The  prepuce  was  edematous  and  phimotic. 
The  glans  penis  showed  numerous  shallow,  small  ulcerations  and 
scars.  The  abdomen  contained  about  100  c.c.  of  a  reddish  brown, 
but  clear  fluid.  The  pleural  cavities  were  filled  with  a  similar 
fluid.  The  pericardial  cavity  contained  a  considerable  amount 
of  a  clear,  straw-colored  fluid.  There  were  no  pleural  adhesions. 
The  lungs  collapsed  partially  when  the  thorax  was  opened.  The 
left  weighed  700  gms. ;  the  right  weighed  975  gms.  Aside  from  a 
moderate  edema  at  the  posterior  parts,  these  organs  showed 
nothing  remarkable. 

The  liver  weighed  1,525  gms.  It  was  of  firm  consistence, 
elastic,  and  of  a  pale  brownish  color.  Section  showed  a  gener- 
ally mottled  appearance,  due  in  part  to  the  presence  of  small 


W  O  O  L  L  E  Y     A  N  D     N  E  W  B  LJ  R  G  H  21 

hyaline  "bacony"  areas,  which  became  brown  after  treatment  with 
iodine. 

The  spleen  was  a  typical  "sago"  spleen  of  moderate  size. 

The  kidneys  weighed  185  gms.  each.  They  were  firm  and 
elastic,  the  cortex  generally  increased  in  thickness,  and  the  glo- 
meruli visible  as  small,  hyaline,  shining  points.  Treatment  of  the 
cut  surface  with  iodine  gave  the  amyloid  reaction.  Both  organs 
were  purplish-red  in  color. 

The  heart  was  enlarged,  pale  and  flabby.  Under  the  visceral 
pericardium,  near  the  base  on  the  right  side,  were  very  numerous 
petechial  and  a  few  very  minute  grayish,  translucent  spots  that 
resembled  in  a  general  sort  of  way  miliary  tubercles.  Both 
cavities  were  dilated.  The  left  ventricle  was  both  dilated  and 
hypertrophied.  At  the  apex  the  myocardium  was  generally  and 
almost  completely  replaced  by  fibrous  tissue.  The  papillary  mus- 
cles were  somewhat  fibrotic. 

The  cardiac  valves  showed  no  evident  abnormalities.  The 
tricuspid  orifice  admitted  tlie  tips  of  four  fingers,  the  mitral  three, 
the  aortic  almost  two.  In  diameter,  the  tricuspid  valve  meas- 
ured 6  cm.,  the  mitral  5  cm.,  the  aortic  3  cm. 

The  aorta  was  the  seat  of  a  well  marked,  extensive  and  se- 
vere grade  of  arteriosclerosis,  of  apparently  syphilitic  origin,  as 
indicated  by  the  bluish  hyaline  thickenings.  Just  above  the 
mouth  of  the  left  coronary  artery  was  the  opening  of  an  aneur- 
rismal  sac,  that  measured  5  cm.  in  diameter.  The  sac  itself  was 
7  cm.  in  its  largest  diameter.  In  it  were  no  clots.  The  walls 
were  irregularly  sclerotic,  with  scattered  hyaline  plaques  and  athe- 
romatous ulcers. 

The  aneurism  projected  laterally  to  the  left,  and  was  adherent 
to  the  pulmonary  artery,  into  which  there  were  two  openings  at 
a  point  about  1  cm.  above  the  junction  of  the  posterior  and  left 
pulmonary  leaflets.  The  openings  measured  1x2  cm.,  and 
1x2  mm.  in  diameter.  The  margins  of  both  were  smooth,  and 
showed  no  evidence  of  recent  rupture.  The  pulmonary  artery 
show'cd  both  fatty  degeneration  and  hyaline  sclerosis,  especially 
in  the  immediate  neighborhood  of  the  aneurismal  openings.  The 
openings  in  the  pulmonary  artery  were  1  cm.  above  the  junction 
of  the   posterior   and   left  pulmonary   leaflets. 

Anatomical  Diagnosis. — Aortic  aneurism  znth  perforation 
inio  the  pulmonary  artery.  Syphilitic  aortitis;  amyloidosis;  pas- 
siz'e  congestion  of  the  liver,  kidneys  and  spleen;  hypertrophy  and 
dilation  of  the  heart;  pleural  and  p erica rdnal  effusion;  edema  of 
the  lungs. 

In  order  to  make  comparisons  easier  and  perhaps  more  odious, 
we  have  composed  the  following  tabulation  of  the  cases  of  which 


22  D  -\  X  D  R  1  D  G  E    AJ  E  AI  O  R  I  A  L 

we  have  been  able  to  find  records.  In  this  tabulation  the  cases 
discussed  by  Kappis  are  included  as  well  as  others,  which,  for  one 
reason  or  another,  were  excluded  from  his  records. 

An  analysis  of  these  cases  brings  out  several  interesting  points. 

1.  Perhaps  most  striking,  is  the  frequency  with  which  the  per- 
foration was  not  the  immediate  cause  of  death.  The  character  of 
the  perforation  was  noted  in  twenty-eight  cases.  Thirteen  times 
(Nos.  5,  6,  12,  15.  18,  19,  25,  30,  34,  36^  39,  42,  49)  the  edges  are 
described  as  smooth  and  rounded,  and  twice  as  thickened  ( Xo£. 
27.  28.).  In  all  but  eleven  cases,  then,  the  perforation  was  pre- 
sumably old;  that  is,  it  was  not  the  im'mediate  cause  of  death  nor 
did  it  even  cause  enough  mischief  to  make  its  presence  suspected. 
This  seemingly  remarkable  fact  is  explained  without  much  diffi- 
culty. When  one  considers  that  the  condition  produced  by  per- 
foration of  an  aortic  aneurism  into  the  pulmonary  artery  gives 
rise  to  a  state  mechanically  very  similar  to  that  produced  by  an 
open  ductus  Botalli,  and  that  the  latter  condition  is  compatible 
with  years  of  comfortable  and  happy  existence,  the  fact  under 
discussion  seems  quite  plausible.  There  is  no  reason  why  the 
perforation,  in  and  of  itself,  should  be  accompanied  by  stormy 
symptoms ;  for  the  change  in  the  circulation  comes  about  so  slowly 
that  there  is  time  for  readjustment. 

In  thirteen  cases  there  was  a  history  of  acute  symptoms  rapidly 
followed  by  death  (Nos.  1,  2,  4,  9,  12,  17,  19,  23,  31,  41.  44,  45, 
48),*  and  in  nine  of  these  the  terms  "jagged,"  "laceration,"  "ir- 
regular," "recent,"  and  "tear"  were  used  to  indicate  the  condition 
of  the  communication  between  the  aneurism-  and  the  pulmonary 
artery,  or  ventricle.  In  No.  19  the  opening  was  described  as 
"healed,"  and  in  this  case  the  sudden  death  should  more  properly 
be  ascribed  to  sudden  cardiac  insufficiency,  and  not  immediately  to 
the  aneurismal  condition.  In  three  (Nos.  23,  44.  45)  the  condi- 
tion of  the  opening  was  not  described.! 

*  In  five  cases  there  was  more  than  one  perforation  ( Nos.  6,  7,  12,  14. 
30),  and  in  but  one  of  these  (No.  12)  were  there  acute  symptoms,  al- 
though another  (No.  30)  showed  evidence  that  it  was  very  recent. 

t  The  ridiculous  variation  in  anatomic  descriptive  terminology  is  no- 
where, we  suspect,  better  illustrated  than  in  this  series  of  cases.  In  esti- 
mating the  size  of  the  aneurismal  sacs  the  word  oranse  is  used  five  times 
(Cases  1,  2,  21,  45,  4)  ;  walnut  seven  times  (Cases  10,  14,  17,  20,  22,  35, 
40)  ;  egg  seven  times  (Cases  8,  12,  13,  37,  38,  18,  24)  ;  fist  twice  (Cases  4, 
31),  and  so  on.  In  but  four  cases  are  the  measurements  given  in  terms 
of  inches  or  centimeters  (Cases  29,  29,  30,  48). 


W  O  O  L  L  E  Y     AND     N  E  W^  B  U  R  G  H  22> 

The  complete  diagnosis  was  made  in  only  three  cases  (12,  ZV, 
48),  and  only  eight  times  was  aortic  aneurism  diagnosed  ante 
mortem.  This  was  undoubtedly  due  to  the  absence  or  masking 
of  the  classic  symptoms  of  aneurism.  And  they,  in  turn,  were  ab- 
sent so  frequently  on  account  of  the  smallness  and  position  of 
the  aneurism.  As  pointed  out  by  Kappis,  the  sac  was  frequently 
described  as  the  size  of  a  walnut,  and  was  almost  always  close  to 
the  heart.  The  perforation  opened  below  the  bifurcation  of  the 
pulmonary  artery  in  all  but  six  cases  (Nos.  16,  18,  23,  25,  31,  49), 
in  which  it  opened  into  the  right  branch,  and  one  case  (No.  3), 
in  which  the  com.munication  was  with  the  left  branch.  Hence, 
in  most  cases,  it  was  not  large  enough  to  cause  distinct  pressure 
symptoms,  and  whatever  dulness  it  produced  must  have  fused 
almost  imperceptibly  with  that  of  the  heart. 

The  sacs  presumably  remained  small  because  they  were  re- 
lieved of  the  brunt  of  the  high  aortic  pressure  earlier  than  in  the 
commoner  forms  of  aneurism,  because  of  the  fact  that  the  sacs 
in  the  cases  pointed  in  such  a  direction  that  erosion  and  rupture 
of  the  pulmonary  artery  occurred  at  an  unusually  early  stage  of 
the  development  of  the  aneurism.  It  is  also  quite  possible  that 
had  the  conditions  in  the  pulmonary  artery  been  described,  evi- 
dence of  preparation  for  rupture  on  the  pulmonary  side  would 
be  available.  Unfortunately,  however,  the  condition  of  the  pul- 
monary artery  is  described  in  but  two  cases ;  in  one  it  was  pitted 
and  rough,  in  the  other  normal  in  appearance.  Howe\^er  this 
may  be,  there  is  evidence  that  the  rupture  occurs  slowly,  and 
that  a  little  blood  is  diffused  from  the  aorta  into  the  pulmonary 
artery  through  the  unruptured  wall  because  of  its  increased  per- 
meability; then  a  minute  opening  forms,  and  this  enlarges  rap- 
idly and  sufficiently  to  relieve  the  high  pressure.  The  walls  of 
the  aperture  become  smooth  and  healed,  because  there  is  no  fur- 
ther mechanical  occasion  for  enlargement,  and  the  process  of 
rupture  comes  to  an  end.  In  such  a  way  an  event  which  ordi- 
narily causes  the  most  disastrous  results  when  it  occurs  in  other 
locations  becomes  a  salutary  one.  The  patient  goes  on  living  for 
weeks  or  months  until  death  comes  as  the  result  of  myocardial 
degeneration,  valvular  lesions,  or,  associated  with  these  and  with 
a  more  severe  arterial  condition,  another  perforation  or  rupture. 


24  DANDRIDGE    MEMORIAL 

Now  that  we  have  accounted  for  the  possibihty  of  the  absence 
of  signs  of  aneurism,  let  us  briefly  consider  the  cases  in  which 
these  signs  were  not  absent. 

Tumor  is  mentioned  but  four  times  (11,  14,  32,  38)  ;  tracheal 
tug  twice  (Nos.  32,  41)  ;  recurrent  laryngeal  paralysis  (No.  32) 
and  the  metallic  cough  (No.  14)  each  once.  Irregularity  of 
pulses  or  pupils  is  not  recorded  once.  Of  the  remaining  signs 
we  find  thirty-two  cases  (Nos.  5,  7,  8,  10,  11,  12,  13,  14,  15,  16, 
18,  19,  20,  22,  23,  24,  25,  26,  27,  28,  29,  31,  32,  33,  34,  35,  36,  37, 
38,  39,  42,  47)  in  which  there  were  murmurs,  thrills  or  pulsating 
tumors  over  the  upper  chest,  either  along  the  left  border  of  the 
upper  sternum,  over  the  manubrium,  or  occasionally  along  the 
right  side  of  the  upper  sternum.  If  we  exclude  those  cases  which 
died  too  shortly  after  entrance  to  a  hospital  to  have  received  suf- 
ficient study,  we  find  that  three-fourths  of  the  cases  presented 
signs  referable  to  disease  of  the  valves  at  the  base  of  the  heart 
or  the  root  of  the  aorta  and  pulmonar}^  artery. 

Kappis  states  that  the  combination  of  sure  signs  of  aortic 
aneurism  with  continuous  murm.urs  or  thrills  is  pathognomonic 
of  two  conditions — the  one  under  consideration,  and  perforation 
of  aneurism  of  the  aorta  into  the  right  ventricle.  The  latter  is 
much  rarer  than  the  former,  and  in  the  present  series  existed 
coincidently  with  the  pulmonary  lesion  in  four  cases  (7,  12,  33, 
35).  When  continuous  murmurs  or  thrills  occur  in  the  absence 
of  sure  signs  of  aneurism,  open  ductus  Botalli  should  be  con- 
sidered first.  This  can  be  excluded  frequently  by  obtaining  a 
careful  past  history.  Unfortunately,  continuous  murmurs  were 
noted  in  only  ten  cases  (Nos.  7,  12,  19,  33,  37,  39,  10,  28,  38,  42), 
Two  of  these  were  cases  in  which  a  correct  diagnosis  was  made 
(12,  17). 

Can  we  find  no  aids  to  the  correct  diagnosis  when  the  murmur 
or  thrill  is  not  continuous?  It  will  be  seen  by  an  inspection  of 
the  pathological  material  that  in  a  considerable  number  of  the 
cases  (8,  13,  19,  27,  29,  32,  37,  38,  35,  43,  47)  the  pulmonary 
artery  or  valves  were  afifected  as  well  as  the  aorta.  Many  of  the 
systolic  murmurs  and  thrills,  especially  those  over  the  manu- 
brium and  along  the  right  border  of  the  sternum,  must  have  sug- 
gested lesions  of  the  pulmonary  valves.     Since  acquired  pulmo- 


Tabulated  Record  of  Forty-nine  Cases  of  Aortic  Aneurism  with  Rupture  into  Pulmonary  Artery     WooUey  and  Newburgh. 


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WOOLLEY     AND     NEWBURGH  25 

nary  stenosis  or  regurgitation  is  so  rare,  aortic  aneurism  opening 
into  the  pulmonary  artery  should  certainly  enter  into  the  differ- 
ential diagnosis. 

Kappis  emphasizes  the  fact  that  almost  all  of  the  cases  pre- 
sented symptoms  of  severe  heart  disease  of  short  duration,  or 
commencing  rather  abruptly  (only  five  cases  lasted  over  one 
year).  The  patient's  age  is  mentioned  forty-eight  times.  In  about 
45  per  cent,  of  the  cases  they  were  less  than  forty,  in  about  80 
per  cent,  of  the  cases  they  were  less  than  fifty,  the  youngest 
twenty-two.  Four  of  the  patients  were  women,  two  of  whom 
were  less  than  thirty. 

Grouping  these  data  together,  the  following  conclusions  seem 
warranted :  When  young  individuals  who  have  never  had  rheuma- 
tism, and  who  do  not  give  a  history  of  congenital  heart  disease, 
present  symptoms  of  severe  heart  disease  of  short  duration,  the 
presence  of  murmurs,  thrills  or  pulsation  referable  to  disease  of 
the  pulmonary  artery  should  make  one  think  of  aortic  aneurism 
perforating  into  the  pulmonary  artery.  If  the  murmurs  are  con- 
tinuous and  any  of  the  signs  of  aneurism  can  be  detected,  the 
diagnosis  may  be  made  with  a  large  degree  of  certainty.  If  these 
murmurs  are  not  continuous,  and  signs  of  aneurism  are  found, 
the  diagnosis  is  probable.  If  there  are  no  signs  of  aneurism,  and 
the  murmurs  are  not  continuous,  one  can  scarcely  do  more  tbm 
suspect  the  condition. 


SOME    NEW    INTERNAL   PARASITES   OE   THE   CALI- 
FORNIA  GROUND   SQUIRREL    (OTOSPERMO- 
PHIL  US  'beech E ] "/. }  * 


BY   CKEIGHTON    WELLMAX, 
OAKLAND,  CAL. 

AND  WM.  B.  WHEKKV. 
CINCINNATI,  O. 


While  examining  last  year  some  California  ground  squirrels, 
we  found  among  this  rodent's  endoparasites  the  following  pro- 
tozoa, worm  and  mite,  which  appear  to  be  new.  Ordinarily  the 
mere  recording  of  new  species  of  the  parasites  of  wild  animals 
is  of  little  interest  to  physicians,  but  since  the  role  played  by 
O.  bcecheyi  in  the  maintenance  of  plague  on  our  Pacific  Coast 
was  definitely  established  {vide  Wherry,  Journal  Infectious  Dis- 
eases, 1908,  V.  485)^  all  medical  men  are  naturally  interested  in 
the  diseases  which  affect  this  rodent.  Therefore  the  following 
brief  descriptions  of  the  parasites  we  have  found  are  offered : 

Protozoa. 
Genus  Leucocytozoon  Danilewsky. 
Leucocytozoon  citellicola  sp.  nov. 

Forms  corresponding  to  trophozoits  were  present  in  consider- 
able numbers  in  smears  from  the  lungs,  spleen,  liver  and  ingui- 
nal glands.  They  were  found  almost  entirely  within  the  polymor- 
phonuclear and  transitional  leucocytes.  Occasionally  they  were 
extracellular.  They  were  best  demonstrated  with  carbol  thionin 
as  they  were  surrounded  by  a  capsular  substance  which  usually 
resisted  Wright's  or  Jenner's  stains.  Prolonged  staining  with 
Giemsa  gave  good  results.  In  form  they  are  elongated,  ovoid, 
sometimes  slightly  curved,  with  a  rather  large  nucleus  which 
stains  uniformly  and  deeply  purple  with  Giemsa  after  methyl 
alcohol  fixation,  but  appear  reticulated  or  granula-  after  heat  and 

*  From  Parasitology,  vol.  m.  No.  4,  December  30,  1910. 

27 


28  DANDRIDGE    AI  E  M  O  R  I  A  L 

carbol  thionin.  The  nucleus  is  often  eccentric.  The  protoplasm 
is  slightly  reticulated  and  filled  with  basophilic  granules  after 
heat  and  carbol  thionin,  and  shows  fine  scattered  reddish  gran- 
ules after  Giemsa.  Aleasurements  gave  slight  variations,  the 
average  being  about  16/x  x  6,u.  A  few  larger  forms  were  seen 
in  smears  from  the  lungs  of  squirrel  2.  These  were  extra- 
cellular, non-encapsulated,  20/x  x  lOfi,  oval,  with  reticulated  pro- 
toplasm and  nucleus  composed  of  isolated  masses  of  chro- 
matin. 

Type  in  the  collection  of  Wm.  B.  Wherry. 

Host. — This  Lcucocytozoon  was  found  in  two  ground  squirrels 
collected  in  July  and  August,  1909;  one  of  these  was  also  infected 
with  a  trypanosome. 

Squirrel  i. — Half-grown  female;  shot  in  the  Berkeley  Hills; 
appeared  normal  upon  dissection  with  the  exception  of  a  slight 
congestion  of  the  inguinal  glands.  Leucocytozoa  were  found, 
chiefly  within  the  polymorphonuclear  and  transitional  cells  in 
smears  from  the  lung,  liver,  spleen  and  inguinal  glands. 

Squirrel  2. — Male,  about  one-third  grown ;  shot  in  the  Pied- 
mont Hills.  It  appeared  to  be  very  ill  and  made  no  effort  to  es- 
cape from  the  hunter.  Post-mortem,  the  organs  showed  no  note- 
worthy changes,  excepting  irregular,  scattered  areas  of  congestion 
in  the  lungs.  Smears  from  the  lungs  showed  no  bacteria,  but 
numerous  motile  trypanosomes  were  seen.  Leucocytozoa  resem- 
bling those  in  squirrel  1  were  found  in  smears  from  the  lungs, 
spleen  and  liver. 

Remarks. — As  far  as  we  know,  the  recent  work  of  Miller 
{Bull.  46,  Hyg.  Lab.  U.  S.  Pub.  Health  and  Marine  Hasp.  Serv., 
1908)  on  Hcpatozoon  perniciosum-  of  the  white  rat  has  not  yet 
been  confirmed,  and  as  we  cannot  say  whether  or  not  schizogony 
takes  place  in  the  liver  of  the  ground  squirrel,  we  have  retained 
the  term  Leuco^cytozoon.  (See  also  Patton,  Parasitology,  1909,  ii, 
144.)  No  evidence  of  schizogony  was  found  in  the  liver  smears, 
and  the  only  body  resembling  a  vermicule  was  found  in  a 
spleen  smear.  It  might  be  mentioned,  since  there  is  a  commu- 
nication between  rats  and  ground  squirrels,  that  this  Leticocy- 
tozoon  is  somewhat  larger  and  differs  in  detail,  e.g.,  nuclear  struc- 


WELLMAN     AND     WHERRY  29 

ture,  from  a  similar  parasite  which  is  commonly  found  in  the 
Norway  rat  (M.  norvegicus)  on  the  Pacific  Coast.  This  para- 
site of  the  rat  corresponds  in  size  and  nuclear  structure  with  H. 
perniciosum  Miller. 

Genus    Trypanozoon   Liihe. 

Trypanosoma  Auctt. 

Trypanozoon  otospermophili  sp.  nov. 

These  parasites  in  squirrel  2  were  actively  motile  and  superfi- 
cially resembled  T.  lezvisi.  After  methyl  alcohol  and  Giemsa  the 
total  length  was  29.5 /a;  from  the  pointed  posterior  end  to  the 
kinetonucleus  1.9/1*;  kinetonucleus  0.6 /x;  from  the  kinetonucleus 
to  the  posterior  end  of  the  nucleus  9  p.;  nucleus  1.8 /x;  from  the 
nucleus  to  the  end  of  the  flagellum  \6p.  ;  greatest  breadth  1.5 /x. 

Type  in  the  collection  of  Wm.  B.  Wherry. 

Host. — California  ground  squirrel   (squirrel  2). 

Remarks. — Two  young  white  rats  and  a  guinea-pig  free  from 
trypanosomiasis  were  injected  intraperitoneally  with  a  physio- 
logical salt  solution  emulsion  of  the  lung  of  squirrel  2.  Their 
blood  was  examined  for  trypanosomes  every  other  day  during  the 
month  of  August  with  negative  results.  The  white  rats  died  on 
August  28  and  30,  but  no  cause  of  death  was  discovered.  The 
ease  with  which  rats  are  infected  with  T.  leunsi  suggests  that 
our  Trypanozoon  is  different. 

Cestoda. 
Collective  Genus  Cystoceraus. 
Cystoccrcus  portolae  sp.  nov. 

When  fully  extended  the  worm  is  somewhat  pyriform,  the 
small  end  being  the  head-  Neck  very  short,  rostellum  dis- 
tinct, armed  with  two  rows  (which  appear  sometimes  like  one 
row  very  irregularly  placed)  of  typical  rose  thorn  hooks. 
Suckers  round.  Epidermis  transparent,  a  dark  granular 
layer  immediately  beneath  it,  body  tissue  apparently  homo- 
geneous, granular,  containing  large  calcareous  corpuscles.  Meas- 
urements of  a  fully  extended  specimen  as  follows :  Total  length 
1 .2  mm.,  breadth  at  widest  part  0.406  mm.,  diameter  of  suckers 
0.084  mm.,  width  of  rostellum  0.343  mm.,  length  of  rostellum 
0.28  mm.,  width  of  neck  0.21  mm.,  average  length  of  long  hooks 
0.028  mm.,  average   width  of  long  hooks  0.018  mm.,  average 


30  DAN  BRIDGE    MEMORIAL 

length  of  short  hooks  0.019  mm.,  average  width  of  short  hooks 
0.013  mm. 

Type  in  collection  of  Creighton  Wellman. 

Host. — O.  becchcyi  in  small  cysts  in  the  liver  substance. 

Remarks. — This  cystocercus  comes  nearest  to  C.  longicollis 
Rud.,  but  is  easily  told  from  it  by  the  fact  that  in  longicollis  the 
neck  is  longer  than  the  body  and  the  body  darker  than  the  neck, 
which  features  do  not  hold  for  our  species.  The  character  of 
the  calcareous  granules  is  also  a  differential  point,  and  according 
to  Dujardin  (Hist.  Nat.  d.  Helm.  1845)  the  hooks  in  longicollis 
are  different  from  those  of  our  worm. 

C.  longicollis  is  said  to  occur  in  moles  and  voles,  and  the  adult 
{Taenia  crassiccps  Zeder)  to  infest  foxes.  It  is  not  improbable, 
therefore,  as  Dr.  Ransom,  of  V.'ashington,  first  suggested  to  one 
of  us,  that  the  adult  form  of  our  worm  will  be  found  in  coyotes 
or  some  such  animal. 

ACARINA. 

Genus  Cytoleichus  Megnin. 

Cytodites  Megnin. 

Cytolichus  Auctt. 

Cytoleichus  hanksi  sp.  nov. 

Resembles  in  its  general  features  C.  nudus,  Vizioli.  Body 
rounded,  broadly  oval,  whitish,  almost  glabrous,  not  striated,  but 
with  very  fine,  irregular,  faintly  marked  ridges  on  the  epidermis- 
Haustellum  shorter,  broader  and  more  truncate  than  in  nudus, 
Viz.,  broadly  conical,  without  cheeks.  Legs  strong,  narrowly  coni- 
cal, composed  of  five  articles  and  terminating  in  a  non-armed  pul- 
villus  on  a  nearly  transparent  pedicle  and  a  long,  Transparent 
seta.  Sexual  dimorphism  not  well  marked ;  in  the  5  9  a  genital 
pore  (vulva  or  tocostome)  may  be  made  out  in  the  median  line 
between  the  next  to  last  pair  of  legs.  Average  length  0.2  mm., 
average  width  0.15  mm. 

Type  in  the  collection  of  Creighton  Wellman. 

Host. — O.  bcecheyi   (lungs). 

Remarks. — This  species,  the  type  of  which  was  submitted  to 
Mr.  Nathan  Banks,  the  eminent  arachnologist,  and  pronounced 
by  him  to  be  new,  we  place  in  the  Cytoleichidse  on  account  of  the 
longitudinal  genital  aperture  of  the  ?  .  The  specimens  were  found 


WELLMAN     AX^D     WHERRY  31 

July  8,  1909,  occurring  in  large  numbers  in  small  grayish,  rounded, 
slightly  raised  tubercles  on  the  lungs  of  two  specimens  of  ground 
squirrels.  The  tubercles  also  exist  in  the  deeper  lung  tissue.  One 
mite  was  found  in  each  tubercle  examined.  The  presence  of 
mites  belonging  to  this  family  (the  "Sarcoptides  cysticoles"  of 
Megnin)  in  the  lungs  and  other  tissues  of  birds  has  been  known 
since  Gerlach's  observations  in  1859.  An  especial  medical  inter- 
est has  been  added  to  the  family  by  the  finding  by  Castellani  of 
one  species  (C.  sarcoptoides  Cast.)  in  the  omentum  of  a  negro 
(Centralbl.  f.  Bakt.  Abt.  1.  xliii,  p.  Z72.) 

We  have  not  included  in  this  paper  the  ectoparasites  found 
by  us  in  O.  beecheyi.  These  consisted  of  different  fleas,  ticks,  etc. 
Among  the  latter  were  two  very  interesting  species,  one  being 
the  common  Z) ^nmJc<?Mf or  occirf^/jio/w  Neum.,  and  the  other  a  new- 
species  Ixodes  aequalis  Banks  (vide  Entomological  News,  Nov., 
1909,  p.  276).  It  is  to  be  hoped  that  the  ground  squirrel  exam- 
ined by  us  will  be  studied  as  carefully  as  the  rat  has  been,  and  to 
such  a  study  we  contribute  the  facts  contained  in  this  paper. 

REFERENCE. 

1.  See  Parasilology,  vol.  ii,  p.  297  {re  fleas  on  rodents  in  California)  ; 
Journ.  of  Hygiene,  vol.  rx,  p.  1  (anti-plague  measures  in  San  Francisco)  , 
also  Jour,  of  Hygiene,  vol.  x,  No.  4  {re  plague  among  ground  squirrels  in 
Amer>a). 


THE  PATHOLOGY  OF  MASTODITIS  AS  REVEALED  BY 
THE  X-RAY.* 


SIDNEY   LANGK,    M.D,,   B.S. 


The  X-ray  study  of  the  mastoid  region,  which  was  begun  in 
March,  1908,  has  undergone  a  slow,  but  gratifying,  metamorpho- 
sis. Undertaken  with  grave  doubts  as  to  its  practical  vahie,  it  has 
developed  into  a  method  which  rivals  in  its  accuracy  other  recog- 
nized methods  of  physical  examination. 

At  the  inception  of  the  work,  it  promised  at  best  to  show  the 
anatomy  and  the  grosser  chronic  changes  in  the  mastoid  region. 
Then  the  graver  acute  changes  were  registered  on  the  skiagr.^.ni, 
and  later  it  was  found  that  the  milder  acute  mastoid  affections 
yielded  roentgenologic  evidence  of  their  presence.  Within  the 
last  few  months  it  was  discovered  that  in  acute  otitis  media  with- 
out clinical  signs  of  mastoid  involvement,  the  X-ray  would  often 
ohow  clouding  and  falling  up  of  the  ma.stoid  cells  just  back  of  the 
antrum,  which  changes  may  either  recede  or  progress  as  the 
patient  either  recovers,  or  goes  on  to  what  is  chnically  termed 
mastoiditis.  The  X-ray  method  is  presented,  then,  as  a  method 
of  studying  intra  vitam  the  gross  pathology  of  the  mastoid. 

A  correct  roentgenologic  technic  is,  of  course,  the  sine  qua 
non  in  this  work,  and  all  conclusions  should  be  based  upon  tech- 
nically good  plates.  The  method  employed  for  correctly  skia- 
graphing  the  mastoids  was  presented  before  this  section  one 
year  ago.^  Further  details  of  the  X-ray  technic  were  outlined 
by  me  in  a  previous  paper-  and  need  not  be  repeated  here.  In  no 
instance  has  a  technically  good  plate  failed  to  give  valuable  and 
accurate  information.  Barring  those  uncommon  cases  in  which 
the  cortex  over  the  mastoid  is  excessively  thick,  or  in  which  the 
mastoid  cells  are    poorly    developed,    the  X-ray  method  should 

*  Read  in  the  Section  of  Laryngology  and  Otolopy  of  the  American 
Medical  Association,  at  the  Sixty-first  Annual  Session,  held  at  St.  Louis, 
June  10,  1910,  and  reprinted  from  the  Journal  of  the  American  Medical 
Association,  September  3,  1910,  vol.  Iv,  pp.  819-822. 

33 


34  DANDRIDGE   MEMORIAL 

in  every  case  reveal  in  a  gross  way  the  pathologic  status  of  the 
mastoid  process. 

The  question  of  excessive  distortion  of  the  relations  of  the 
mastoid  as  a  result  of  the  obliquity  of  the  rays  was  answered 
by  making  a  series  of  tests  on  the  dried  skull.  Lead  markers 
were  placed  on  the  tegmen,  groove  for  lateral  sinus,  and  mastoid 
tip,  and  measurements  made  from  the  skiagraph  were  compared 
with  the  actual  distances.  In  no  instance  did  the  discrepancy 
exceed  3  mm.,  which  difference  for  practical  purposes  may  be 
disregarded. 

The  interpretation  of  the  skiagram  is  always  based  on  a 
comparison  of  the  diseased  with  the  opposite  normal  mastoid. 
After  repeated  comparisons  in  normal  individuals,  in  no  case  did 
I  find  essential  difierences  between  the  two  normal  mastoids  of 
the  opposite  sides.  While  there  may  be  variations  in  the  size, 
number  and  arrangement  of  the  cells  of  the  two  sides,  the  mas- 
toids as  a  w^hole  were  closely  similar  in  type.  That  is,  if  there 
is  a  pneumatic  mastoid  on  one  side  there  vv^ill  be  a  pneumatic 
mastoid  on  the  other,  or  if  the  one  mastoid  is  of  the  diploetic 
type,  the  opposite  one  will  be  of  the  same  type.  Plageman  says : 
"On  a  basis  of  85  skiagrams  of  normal  skulls,  we  find  that  as  a 
rule  the  two  mastoid  processes  of  healthy  individuals  are  almost 
identical."  Where  both  sides  are  diseased,  more  difficulty  is  en- 
countered in  reading  the  plates,  but  after  a  study  of  many  plates 
a  fairly  accurate  interpretation  may  be  made  of  a  single  plate 
without  a  comparison  with  its  fellow  of  the  opposite  side. 

Previous  inflammation  in  a  mastoid  usually  leaves  permanent 
alterations  in  the  bone,  either  in  the  form  of  more  or  less  exten- 
sive absorption  of  the  mastoid  process  or  sclerosis  of  same,  and 
if  this  inflammation  occurs  in  early  life  the  development  of  the 
mastoid  may  be  so  retarded  as  to  result  in  a  diploetic  or  even 
sclerotic  type.  Therefore,  in  interpreting  mastoid  plates  the  pre- 
vious aural  history  must  be  ascertained. 

On  the  mastoid  skiagrams  of  children  under  ten  years  the 
mastoid  appears  entirely  spongy  or  diploetic,  there  are  few  visi- 
ble cells,  and  the  tip  is  undeveloped.  The  tip  at  this  time  con- 
sists simply  of  an  inner  and  outer  table,  with  little  cancellous 
bone  between,  and  shows  little  structure  on  the  skiagram.    From 


L  A  N  G  E  35 

the  age  of  ten  to  fifteen  the  mastoid  takes  on  the  pneumatic  char- 
acteristics ;  large  cells  appear  and  grow  downward  toward  the 
tip,  its  diploetic  structure  finally  giving  way  to  the  more  or  less 
pneumatic  adult  type.  The  development  of  the  mastoid  may  be 
beautifully  demonstrated  by  a  series  of  successive  skiagrams. 

In  order  to  study  the  mastoid  relations  more  graphically, 
stereoscopic  skiagrams  may  be  made.  For  this  purpose  I  have 
devised  a  small  stereoscopic  platform  by  means  of  which  the  two 
stereoscopic  exposures  may  be  made  on  a  5  x  7  plate.  When 
developed  and  dried  this  plate  may  be  placed  directly  without 
printing  or  reduction  in  a  cheap  parlor  stereoscope  and  viewed  by 
transmitted  light.  This  method  has  not  been  used  as  a  routine, 
because  of  the  fact  that  four  exposures  (two  for  each  mastoid) 
are  required.  A  reluctance  to  make  repeated  exposures  has  in- 
terfered also  in  following  the  clinical  cases  at  various  stages  from 
onset  to  cure.  While  the  danger  of  the  temporary  Roentgen  alo- 
pecia is  a  remote  one,  even  though  the  exposures  be  repeated, 
provided  an  aluminumi  and  leather  filter  be  used,  it  was  thought 
best  not  to  take  the  chance  of  embarrassing  the  work  at  this 
time  by  any  such  untoward  after-eflfects.  Therefore,  in  most  of 
the  patients  examined  but  one  exposure  of  each  side  was  made. 
Just  one  caution  should  be  given  in  regard  to  the  character  of 
tube  best  suited  to  this  work.  The  lowest  or  softest  tube  pos- 
sible should  be  employed.  The  higher  tube  gives  crisper  and 
more  beautiful  pictures,  but  when  we  consider  the  small  size  of 
the  mastoid  cells  and  the  fact  that  we  are  attempting  to  show  all 
the  smallest  septa  and  contents  of  these  cells,  those  tubes  which 
give  beautiful  bone  detail  of  the  heavy  cranial  bones  will  often 
fail  to  show  the  slightest  changes  in  density  in  the  mastoid 
region. 

CLASSIFICATION  OF  PATHOLOGIC  CHANGES. 

The  pathologic  changes  which  may  be  noted  on  a  skiagram 
may  be  tabulated  as  follows : 

1.  Slight  haziness  of  cell  spaces  or  complete  filling  of  same 
with  something  denser  than  air.  These  changes  represent  clin- 
ically otitis  media  with  slight  mastoid  involvement  and  the  milder 
forms  of  mastoiditis.    The  something  which  fills  the  cells  is  in  all 


36  DANDRIDGE    MEMORIAL 

probability  serum.     To  show  these  slight  changes  the  skiagram 
must  be  made  with  a  soft  tube  and  slightly  underexposed. 

2.  Marked  clouding  of  cell  spaces  with  loss  of  distinctness 
and  partial  destruction  of  cell  walls.  Clinically  these  changes 
are  found  in  the  more  severe  grades  of  mastoiditis  with  pus  for- 
mation and  bone  softening. 

3.  More  or  less  complete  loss  of  structure  of  the  mastoid 
process  occurring  (a)  either  in  the  form  of  localized  abscess  for- 
mation, or  (b)  as  is  often  seen  in  the  subacute  cases  in  the  form 
of  diffuse  loss  of  structure,  indicating  advanced  necrosis  of  the 
entire  mastoid  process. 

4.  Increased  bone  density  of  the  mastoid  process  with  (a) 
partial  or  complete  obliteration  of  cells,  and  (b)  with  bone  de- 
fects.    This  class  represents  the  chronic  sclerosed  cases. 

These  changes  will  be  discussed  in  the  reverse  order,  the  or- 
der in  which  they  are  recognized. 

CHRONIC    MASTOIDITIS. 

The  first  report  of  this  work  was  based  entirely  on  the  exam- 
ination of  the  chronic  cases.  The  ease  with  which  chronic 
changes  can  be  shown  on  the  skiagram  offers  a  method  of  deter- 
mining in  any  case  of  chronic  otorrhea  the  gross  pathologic  con- 
dition of  the  mastoid  process.  In  those  cases  in  which  the  cause 
of  the  continued  discharge  cannot  be  determined  by  the  usual 
methods,  the  skiagram  may  give  the  desired  information  by  show- 
ing the  extent  of  the  sclerosis  on  the  one  hand  or  gross  bone 
defects  on  the  other. 

The  skiagraphic  appearance  in  these  cases  is  a  thickening 
and  obliteration  of  cells.  In  older  cases  the  entire  mastoid  pro- 
cess appears  dense  and  structureless,  giving  no  indication  of 
the  presence  of  cells.  From  my  experience  it  would  appear  that 
this  extensive  sclerosis  occurs  frequently  after  mastoiditis  of  a 
mild  and  not  necessarily  long-continued  type,  since  the  sclerosing 
process  is  a  healing  process.  Interesting  to  note  is  the  fact  that, 
in  the  examination  of  supposedly  normal  cases  for  purposes  of 
study,  every  now  and  then  a  markedly  sclerosed  and  often  under- 
sized mastoid  process  would  be  found,  and  no  history  of  previous 
ear  trouble  could  be  elicited  from  the  patient.    These  undersized 


LANGE  37 

sclerotic  types  probably  represent  a  sclerosis,  partial  absorption 
or  retardation  of  mastoid  development,  consequent  to  a  forgotten 
otitis  media  of  early  childhood.  Aside  from  these  occasional 
exceptions  in  all  of  the  markedly  sclerosed  cases,  the  patients 
examined  had  symptoms  in  the  form  of  intermittent  otorrhea. 
To  illustrate  different  phases,  several  cases  will  be  cited  briefly. 

Case  1. — Sclerosis. — A.  V.,  aged  sixteen,  presented  intermit- 
tent discharge  from  the  left  ear,  dating  from  an  attack  of  acute 
otitis  media  three  years  back.  Examination  revealed  a  thick- 
ened drum  with  a  small  perforation  in  the  antero-inferior  quad- 
rant. X-ray  examination  showed  a  sclerotic  mastoid  on  the  left 
side,  with  very  little  evidence  of  cellular  structure.  Subsequent 
operation  verified  the  X-ray  findings.  This  history  is  typical  of  a 
majority  of  chronic  cases  encountered. 

Case  2. — Sclerosis  zvith  Bone  Defect. — J.  Z.,  Italian,  was 
admitted  to  the  Cincinnati  Hospital  because  of  some  pain  and 
tenderness  over  the  mastoid.  Previous  history  could  not  be  ob- 
tained, except  that  the  affected  ear  had  discharged  for  some  time. 
Examination  of  the  canal  revealed  changes  associated  with 
chronic  middle-ear  suppuration.  An  X-ray  examination  of  the 
mastoids  showed  no  cells  on  the  affected  side.  Instead,  the  bone 
seemed  to  be  hollowed  out  just  back  of  the  antrum.  On  opera- 
tion no  cells  were  found,  but  a  large  bone  defect  in  a  small  scle- 
rotic mastoid. 

Case  3. — Suhacitte  Case  tmth  Bone  Softening. — This  is  a  sub- 
acute rather  than  a  chronic  case,  but  is  included  here  because  the 
plate  showed  typical  bone  defects  in  a  thickened  m.astoid,  such 
as  might  be  encountered  in  the  more  chronic  cases :  r.Ir.  C,  aged 
thirty-live,  came  in  from  one  of  the  surrounding  towns  because 
of  continued  discharge  and  pain  over  the  mastoid  dating  back  seven 
weeks.  The  case  had  received  practically  no  treatment.  Examina- 
tion showed  a  perforation  in  the  anterior  inferior  quadrant.  No 
bulging  of  the  canal.  Temperature  was  99.5°  in  the  evening, 
normal  in  the  morning.  Pain  was  marked  especially  at  tip.  The 
patient  was  referred  to  me  for  X-ray  examination,  which  revealed 
an  apparently  thickened  and  structureless  mastoid  except  for  sev- 
eral irregular  areas  of  apparently  more  necrotic  bone  which 
seemed  to  honeycomb  the  mastoid.  Operation  the  following  day 
substantiated  the  diagnosis  in  every  detail. 

SEVERE    ACUTE    MASTOIDITIS. 

Every  case  of  severe  acute  mastoiditis  has  given  distinct  evi- 
dence on  the  skiagram.    The  changes  varied  from  filling  the  mas- 


38  DANDRIDGE    MEMORIAL 

toid  cells  with  something  other  than  air  (serum,  pus  or  granu- 
lations), with  indistinctness  and  partial  disappearance  of  cell 
outlines,  to  circumscribed  abscess  formation  or  diffuse  loss  of 
structure  of  the  mastoid. 

Case  4. — Mrs.  S.  gave  a  history  of  a  running  ear  following 
an  attack  of  influenza.  Discharge  continued  two  weeks  and  then 
stopped.  Two  weeks  later,  or  four  weeks  after  the  onset,  the 
patient  came  under  medical  observation  because  of  pain  over  the 
mastoid,  especially  right.  Examination  revealed  a  thickened 
drum,  no  discharge,  no  perforation,  marked  tenderness  over  mas- 
toid, but  no  redness  or  swelling.  Temperature  was  99°  to  100° ; 
X-ray  examination  revealed  a  hazy  mastoid  whose  cells  were  no 
longer  air-filled  and  septa  partially  broken  down.  Operation  the 
day  following  the  X-ray  examination  verified  the  skiagram. 

Case  5. — Miss  W.,  aged  twenty-five,  had  had  influenza  three 
weeks  previously,  with  a  running  ear,  but  without  pain  or  ten- 
derness over  the  mastoid.  Discharge  continued  for  three  weeks, 
and  patient  finally  sought  medical  attention  because  of  an  in- 
creasing malaise.  Examination  revealed  a  large  perforation  in 
posterior  part  of  drum,  with  scant  or  no  discharge.  There  was 
no  swelling  or  redness  over  the  mastoid,  but  marked  tenderness 
on  deep  pressure  over  antrum,  no  fever.  X-ray  examination 
revealed  a  small  abscess  in  the  mastoid  about  the  size  of  a  hazel- 
nut. The  rest  of  the  mastoid  appeared  hazy  and  indistinct.  Sub- 
sequent operation  verified  this  finding  in  every  detail. 

The  following  case  is  typical  of  a  number  of  cases  observed 
from  the  onset,  in  which  there  were  definite  signs  of  severe  mas- 
toid involvement,  but  in  which  the  operative  indications  were  not 
clear.  Operative  interference  is  often  delayed  in  these  cases 
awaiting  spontaneous  resolution.  The  X-ray  plate  showing  the 
amount  of  destruction  may  be  a  deciding  factor. 

Case  6. — Miss  H.,  a  nurse  at  Cincinnati  General  Hospital, 
aged  thirty,  developed,  incident  to  influenza,  intense  pain  in  the 
ear,  which  in  a  few  hours  was  followed  by  rupture  of  the  drum, 
and  a  profuse  bloody  discharge.  Three  days  later  the  staff 
otologist  was  called  to  see  her  because  of  pain  and  tenderness 
over  the  mastoid.  He  found  a  small  perforation  and  enlarged  it 
by  incision.  Tenderness  and  pain  abated,  and  it  was  thought 
that  recovery  would  follow  in  a  few  days.  Seven  days  later 
there  was  a  recurrence  of  the  pain  and  paracentesis  of  the  drum 
was  again  performed.  The  pain  and  tenderness  now  persisted  in 
moderate  degree,  and  a  week  later  I  was  asked  to  make  a  skia- 


L  A  N  G  E  39 

gram.  The  skiagram  showed  absolutely  positive  evidence  of  a 
breaking  down  of  the  entire  mastoid,  and  the  operation  the  fol- 
lowing day,  almost  three  weeks  after  the  onset,  verified  the 
X-ray  finding. 

MILD  ACUTE  MASTOIDITIS. 

In  the  stud)'-  of  the  milder  acute  cases,  an  interesting  problem 
presented  itself.  By  the  milder  cases  is  meant  those  cases  in 
which  there  are  distinct  demonstrable  changes  in  the  mastoid, 
but  in  which  there  is  little  or  none  of  the  gross  destruction  seen 
in  the  more  severe  cases.  These  cases  may  or  may  not  progress 
to  spontaneous  recovery.  The  first  change  is  that  of  fluid-filled 
cells.  That  is,  the  cell-spaces,  instead  of  standing  out  sharply 
and  clear,  show  by  comparison  with  the  opposite  side  that  the  air 
is  displaced  by  a  more  solid  substance,  which  may  be  serum,  pus 
or  granulations.  The  cell  walls  are  fairly  distinct  and  not  bro- 
ken down.  This  appearance  of  fluid-filled  instead  of  air-filled 
cells  is  very  characteristic  of  this  stage ;  and  in  the  attempt  to 
draw  operative  indications  from  the  plate,  the  question  as  to 
how  much  bone  change  in  the  mastoid  may  occur  without  pre- 
cluding spontaneous  recovery,  that  is,  what  amount  of  skia- 
graphic  bone  change  makes  operation  imperative,  presented  itself. 

Of  course,  I  did  not  attempt  to  decide  such  a  weighty  prob- 
lem. In  discussing  the  same,  the  fact  that  each  text-book  and 
each  specialist  has  individual  ideas  regarding  the  pathology  of 
acute  mastoiditis  was  somewhat  confusing.  Those  of  the  con- 
servative school  cite  many  instances  of  clinically  severe  mas- 
toiditis which  have  recovered  under  the  expectant  treatment, 
whereas  those  of  more  radical  tendencies  advise  early  operative 
interference  when  fairly  positive  clinical  evidence  of  mastoid  in- 
volvement is  at  hand.  The  thought  at  once  suggests  itself,  would 
it  not  be  possible  by  means  of  the  X-ray  to  decide  this  point,  and 
by  a  comparative  X-ray  study  of  a  large  series  of  cases  to  deter- 
mine what  amount  of  bone  destruction  makes  operative  interfer- 
ence imperative,  if,  indeed,  the  question  can  be  settled  at  all? 
Although  my  series  of  cases  is  far  too  small  and  too  incom- 
pletely studied  to  warrant  any  definite  conclusions,  yet  I  adhere 
to  the  following  tentative  rule:  If  in  an  acute  case  the  skiagram 
shows  fluid-filled  cells  with  little  or  no  breaking  down  of  cell 


40  DANDRIDGE    MEMORIAL 

walls,  an  expectant  line  of  treatment  is  suggested,  whereas,  if  the 
bone  destruction  is  definite  and  considerable,  operation  is  rec- 
ommended. 

The  following  two  cases  are  typical  of  this  milder  type  of 
mastoiditis. 

Case  7. — Mrs.  E.,  aged  thirty-five,  had  for  ten  days  suffered 
with  pain  in  the  ear.  Examination  revealed  in  addition  to  in- 
flamed drum,  pain  and  tenderness  over  the  mastoid.  There  was 
some  fever,  100"  in  evening,  99.5°  in  morning.  The  drum  was 
incised,  but  symptoms  continued  a  week  unabated.  An  X-ray 
examination  made  at  this  time  revealed  the  mastoid  cells  fluid- 
filled,  but  little  or  no  bone  change.  After  two  weeks,  discharge 
gradually  ceased  and  mastoid  symptoms  abated.  Drum  returned 
to  normal,  pain  and  fever  disappeared,  whispered  voice  heard  at 
twelve  feet.  A  second  X-ra}'  examination  made  two  weeks  later 
showed  the  afTected  mastoid  apparently  normal,  the  ceils  contain- 
ing air. 

Case  8. — Mrs.  M.,  aged  thirty-three,  suffered  severe  pain  in 
ear,  following  an  acute  rhinitis.  On  examination,  drum  was  bulg- 
ing, covered  with  hemorrhagic  blebs,  mastoid  tender  over  antrum. 
Drum  was  lanced  and  few  drops  of  serum  exuded,  followed  by 
sero-bloody  discharge,  which  continued  three  days,  and  suddenly 
stopped.  Pain  returned.  Drum  was  again  incised,  and  mucoser- 
ous  discharge  continued.  Marked  tenderness  was  present  over 
mastoid  and  antrum,  extending  toward  tip,  but  there  was  no  fever. 
After  several  days  discharge  again  stopped,  and  buzzing  and 
throbbing  pain  was  complained  of.  X-ray  examination  at  this 
stage  revealed  a  haziness  of  the  cells  just  back  of  the  mastoid 
antrum,  but  not  extending  over  the  rest  of  the  mastoid.  The 
slight  changes  seen  in  the  plate  did  net  seem  to  warrant  any  active 
interference.  From  this  time  the  case  went  on  to  recovery,  and  a 
second  plate  made  (two  weeks  after  the  first  one)  showed  appar- 
ently a  restoration  to  the  normal. 

Several  cases  similar  to  these  were  encountered  at  the  Cin- 
cinnati General  Hospital,  but  as  the  patients  treated  here  often  in- 
sist on  leaving  before  entirely  recovered,  and  are  then  lost  track  of, 
the  ultimate  outcome  could  not  always  be  followed.  Of  great 
interest  would  be  some  statistics  as  to  how  frequently  such  mild 
mastoid  involvement  goes  on  to  ultimate  recovery,  and  what  per- 
centage becomes  chronic  or  give  rise  to  intercranial  or  other  com^ 
plications. 


L  A  N  G  E  41 


ACUTE  OTITIS  MEDIA. 


After  this  succe.-s  in  detecting  the  milder  changes  in  the  mas- 
toid a  small  series  of  patients  with  acute  otitis  media  without 
clinical  signs  of  mastoiditis  was  examined.  To  my  surprise  more 
than  50  per  cent,  of  the  patients  skiagraphed  gave  evidence  on 
the  plate  of  slight  mastoid  involvement.  This  involvement  was 
indicated  by  a  slight  haziness  of  the  cells  just  back  of  or  sur- 
rounding the  antrum.  The  bone  contours  were,  however,  sharp 
and  distinct. 

The  X-ray  study  of  the  mastoid  region  is  submitted  at  this 
time  as  an  aid  in  the  obscure  cases.  A  more  extended  study  of  a 
large  series  of  cases  will,  it  is  hoped,  put  this  work  on  such  a 
firm  basis  that  in  any  case  an  X-ray  examination  may  yield  results 
so  valuable  as  to  justify  the  procedure. 

But  the  work  has  a  broader  application.  By  repeated  exami- 
nations the  course  of  a  single  case  may  be  studied.  By  extended 
studies  over  long  intervals  of  months  or  years  some  new  phases  of 
the  pathology  of  mastoiditis  may  be  brought  out.  The  ultimate 
results  of  acute  and  chronic  mastoiditis  in  early  childhood,  their 
influence  on  the  development  of  the  mastoid  and  the  auditory 
function  in  later  life,  the  final  results  of  those  types  of  mastoid- 
itis in  which  the  patients  apparently  recover  without  operation, 
and  the  relation  of  mastoid  sclerosis  to  the  capsule  and  functions 
of  the  internal  ear,  are  problems  on  which  systematic  X-ray  work 
may  possibly  throw  some  light.  As  a  preliminary  to  such  studies 
involving  repeated  exposures,  it  must  first  be  determined  at  what 
intervals  and  how  many  exposures  may  be  safely  given  without 
causing  alopecia  and  what  form  of  technic  will  best  guard 
against  it. 

The  cases  of  acute,  subacute  and  chronic  otitis  media  in  young 
children,  aged  one  to  ten,  presented  such  unique  appearance  on  the 
skiagram  as  to  warrant  special  consideration.  It  was  my  priv- 
ilege to  examine  about  ten  patients  of  this  kind,  who  presented  no 
marked  clinical  signs  of  mastoid  involvement.  Almost  without 
exception  the  mastoid  showed  changes  varying  from  a  slight  hazi- 
ness of  cells  in  the  earlier  cases  to  more  or  less  bone  destruction 
in  the  more  severe  cases,  while  the  chronic  ones  showed  pro- 


42  D  A  N  D  R  I  D  G  E     U  E  ^i  O  R  I  A  L 

noiinced  sclerosis.  Owing  to  tbei  small  size  of  the  cells  and  the 
immature  development  of  the  mastoid,  the  amount  of  bone  change 
is  often  hard  to  determine  in  these  cases.  In  evei"y  case,  how- 
ever, in  which  such  haziness  of  the  mastoid  was  evident,  if  opera- 
tion was  subsequently  performed  actual  mastoid  involvement  was 
found,  justifying  operation.  It  would  appear  that  in  a  majority 
of  cases  otitis  media  in  early  childhood  is  accompanied  by  distinct 
mastoid  involvement.  As  mentioned  above,  the  small  size  of  the 
mastoid  in  these  cases  made  it  rather  difficult  to  draw  operative 
indications  from  the  plate. 

referencp:s. 

1.  Iglauer,    S. :    The    Qinical   Value   of   Radiography    of    the   Mastoid 
Region.    Journal  A.  M.  A.,  September  25,  1909,  p.  1005. 

2.  American  Quarterly  Roentgenology,  December,  1909,  No.  1,  ii. 


MINERS'  CONSUMPTION/ 


BY  OTTO  V.  HUFFMAN,  M.D. 


Miners'  consumption  is  a  term  used  by  the  miners  to  designate 
emaciation  associated  with  anemia,  general  weakness,  shortness 
of  breath  and  occasionally  palpitation.  It  is  distinctly  a  layman's 
term  for  a  general  condition  which  may  be  due  to  a  variety  of 
causes.  Whoever  has  observed  a  large  number  of  miners  must 
have  been  struck  with  the  fact  that  the  majority  are  pale  and 
thin,  and  that  they  present  the  facies  of  chronic  dyspepsia.  A 
low  state  of  health  among  miners  is  so  prevalent  and  the  use  of 
the  term  "miners'  consumption"  so  general  that  the  subject  mer- 
its the  serious  attention  of  the  medical  profession. 

One  does  not  have  to  look  far  for  causes  of  ill-health  among 
miners.  Most  mines  and  mining  towns  are  without  any  sanitary 
measures  whatsoever.  In  the  mine  urine  and  feces  are  disposed 
of  promiscuously.  The  miner's  home  is  situated  anywhere.  The 
outhouse  is  nearly  always  on  the  hillside  above  the  home,  and  of 
course  the  well  below.  The  women  and  children  seem  to  thrive 
regardless  of  filthy  practices,  however,  so  we  must  look  into  the 
mine  where  the  miner  works  for  the  direct  cause  of  his  condition. 

According  to  the  returns  of  the  twelfth  census  there  were  528,- 
822  persons  in  continental  United  States  reported  as  "miners"  in 
the  year  1900.  Of  this  number  344,205  were  reported  as  coal 
miners ;  52,024  as  gold  miners  and  silver  miners,  and  132,593  as 
miners  not  specified. 

Analyses  reported  by  the  Technological  Division  of  the  United 
States  Geological  Survey  show  that  the  atmosphere  at  the  face  of 
the  coal  in  the  mine  contains  nearly  always  traces  of  ethane,  me- 
thane and  carbon  monoxid  gases.  In  the  ordinary  management 
of  a  mine  means  are  taken  to  detect  these  gases  before  they  are 
present  in  such  a  dangerous  degree  as  to  become  inflammable. 
Efficient  forced  ventilation  will  usually  remove  the  gases  in  suffi- 

*  Reprinted  from  The  Journal  of  the  American  Medical  Association, 
November  26,  1910,  vol.  Iv.  pp.  1891-1892. 

43 


44  DANDRIDGE    MEMORIAL 

cient  quantity  to  minimize  the  danger  of  an  explosion,  but  at  the 
face  of  the  coal  where  the  miner  is  working,  there  will  always 
be  traces  of  the  above-mentioned  gases.  The  stronger  the  ven- 
tilation the  greater  the  tendency  to  exhaust  in  the  rooms  and  blind 
entries,  with  greater  liberation  of  gases  from  the  newly-made 
cuts,  bore-holes  and  broken  coal.  In  just  what  way  the  delete- 
rioijs  effects  of  ethane  and  methane  are  brought  about  when  in- 
haled in  small  qua,ntities  over  a  long  period  we  are  not  prepared 
to  say,  but  we  do  know  that  carbon  monoxid  has  the  property 
of  uniting  with  the  hemoglobin  of  the  red  blood  corpuscles  to 
form  a  rather  stable  compound,  and  that  it  is  not  readily  replaced 
by  oxygen. 

In  mines  where  dynamite  and  other  nitroglycerin  explosives 
are  used  we  have  another  source  of  poison.  In  such  explosives 
the  nitroglycerin  is  mixed  with  inert  matter.  As  a  result  of  an 
explosion  the  inert  matter  is  blown  into  the  ore  or  coal.  Adher- 
ing to  the  particles  of  this  inert  matter  are  small  amounts  of  nitro- 
glycerin which  have  been  disseminated  without  entering  into  the 
detonation — being  finnly  fixed  to  the  particles  of  the  menstruum, 
like  so  many  tablets  of  nitroglycerin.  Later  this  dust  containing 
small  amounts  of  nitroglycerin  is  inhaled  during  loading  or  shovel- 
ing, and,  as  every  physician  knows,  the  most  efficacious  way  of 
administering  nitroglycerin  is  to  dissolve  the  triturate  in  the 
mouth.  Another  way  of  absorbing  this  poison  is  through  the 
skin.  Hence,  these  miners  complain  of  headache,  palpitation  and 
nausea.  Sometimes  men  working  on  the  tipple  cut  in  the  open 
complain,  too,  as  they  breathe  this  dust  when  the  cars  or  wagons 
are  dumped. 

During  the  past  year  Congress  passed  a  law  establishing  a 
Bureau  of  Mines  on  account  of  the  great  number  of  miners  killed 
or  maimed  annually  as  a  result  of  a  lack  of  safety  devices.  It  may 
be  opportune  for  the  physicians  to  make  some  effort  to  better  the 
condition  of  the  miner  from  a  hygienic  and  sanitary  standpoint. 
If  in  one  of  our  naval  ships  we  did  not  have  elaborate  sys- 
tems of  ventilation  and  did  not  make  careful  tests  for  the  least 
increase  in  carbon  dioxid  gas  for  the  several  hundred  men  con- 
fined below — if  we  did  not  prohibit  promiscuous  expectorating, 


HUFFMAN  45 

urinating  and  defecating,  what  a  deplorable  ship  and  state  of 
health  we  should  have ! 

It  is  no  less  important  to  have  a  clean,  well-ventilated  mine  for 
the  several  hundred  men  working  in  it.  The  mere  fact  that  the 
filth  is  hidden  in  darkness  is  no  excuse  for  permitting  a  lack  of 
sanitary  precautions  which  we  would  not  countenance  one  mo- 
ment in  the  open  light.  We  should  provide  our  mines  with  better 
ventilation  and  more  experts  capable  of  analyzing  the  air. 

Physicians  in  mining  towns  are  without  authority.  It  seems 
as  though  it  might  come  within  the  province  of  this  new  bureau 
to  make  rules  in  regard  to  sanitary  measures  outside  the  mine  as 
well  as  inside.  Without  chronic  gas  poisoning,  typhoid,  tubercu- 
losis, hookworm,  chronic  nitroglycerin  poisoning,  and  other  pre- 
ventable diseases,  as  well  as  fleas  and  chiggers,  perhaps  there 
would  be  no  "miners'  consumption." 

Some  physicians  jump  to  the  conclusion  that  the  miner  has 
general  pulmonary  fibrosis  (anthracosis).  As  a  matter  of  fact,  the 
miner  of  to-day  inhales  very  little  dust,  much  less  than  the  coal- 
handlers  outside  inhale,  and  he  does  not  have  evidences  of  ca- 
tarrhal inflammation  of  the  respiratory  tract  to  the  same  degree 
as  the  men  working  in  coal  dust,  who  undoubtedly  have  an- 
thracosis. 

Other  physicians  account  for  the  miner's  pallor  by  the  lack 
of  sunshine,  without  considering  real  anemia.  Many  men  have 
continued  to  work  in  dark  but  well-ventilated  places  other  than 
mines  for  many  years  without  developing  anemia  or  marked 
pallor. 

It  is  our  duty  to  conduct  some  serious  investigations  in  regard 
to  the  health  of  our  miners.  We  should  have  more  data  at  hand 
obtained  from  blood-examinations,  post-morten  examinations,  air 
analyses  and  other  examinations  which  may  give  us  exact  in- 
formation. 


THE  WASSERMANN  REACTION.-^^ 


BY  OSCAR  BERGHAUSEN,   A.li.,    M.D. 


The  serum  diagnosis  of  syphilis  has  stood  the  test  of  five  years, 
and  is  now  being  universally  employed.  In  a  recent  German  con- 
gress the  question  as  to  the  relative  value  of  the  original  method 
and  its  various  modifications  was  brought  up,  and  the  discoverer 
naturally  insisted  upon  his  original  method  being  adopted  as  the 
standard.  The  only  modification  which  is  being  successfully 
applied  is  that  introduced  by  Noguchi.  Von  Dungern  has  intro- 
duced the  same  method  into  Germany,  and  is  still  maintaining  its 
value,  despite  the  criticism  of  the  Wassermann  school. 

That  differences  should  exist  in  the  examination  of  various 
sera  by  different  experimenters  is  not  to  be  wondered  at,  when 
the  difficulties  of  the  reaction  are  taken  into  consideration.  Mis- 
takes are  made  in  interpreting  the  doubtful  or  border-line  reac- 
tions when  nothing  is  clinically  known  of  the  case.  Five  variable 
factors  must  be  worked  with,  and,  unless  all  steps  are  properly 
carried  out,  errors  may  follow.  This  is  shown  by  the  various 
reports  sent  in  by  Berlin  workers,  when  serum  from  the  same 
patient  was  sent  to  different  men  for  analysis.  A  preferred  stu- 
dent of  Wassermann  was  guilty  of  interpreting  a  positive  case  as 
negative,  and  on  another  occasion  a  negative  case  as  positive. 
Even  the  most  expert  must  exercise  extreme  care  to  avoid  such 
errors.  The  reaction  is  not  one  for  every  person  to  carry  out, 
unless  he  has  the  requisite  knowledge  of  hemolysis  and  the  abil- 
ity to  work  persistently  and  constantly.  Ordinary  help,  trained 
to  do  the  reaction,  do  the  work  in  a  methodical  way,  without  a 
full  realization  of  the  various  biological  factors  which  must  be 
taken  into  consideration.  The  various  products,  especially  hemo- 
lytic amboceptor,  antigen  and  complement,  must  be  thoroughly 
examined  before  each  examination  to  avoid  discrepancies.  To 
perform  the  reaction  with  the  same  amounts  on  Friday  as  were 

*  From  The  Lancet-Clinic,  December  17,  1910. 

47 


48  DANDRIDGE    MEMORIAL 

used  on  the  previous  Tuesday    would  be  wrong,  unless  previous 
experiment  would  have  shown  this  to  be  proper. 

To  avoid  errors  in  interpretation,  the  writer  has  employed  vari- 
ous methods  of  late,  in  order  to  give  him  a  wider  range  and  to  un- 
derstand their  rela*:ive  value.  The  Noguchi  and  the  original 
Wassermann  method  are  the  only  two  which  need  be  thoroughly 
considered. 

THE  COMPLEMENT. 

Noguchi  deserves  great  credit  for  establishing  clearly  the  im- 
portance of  taking  into  consideration  the  relative  values  of  com- 
plement and  hemolytic  amboceptor  before  each  test.  Ordinarily, 
in  the  original  method,  one-tenth  cubic  centimeter  of  guinea-pig 
serum  is  taken  as  a  standard  amount  of  complement  for  each  test. 
The  relative  amount  of  hemolytic  amboceptor  for  one  unit  of 
complement  is  determined  and  then  doubled  before  using  in  the 
final  test.  In  the  Noguchi  modification,  when  properly  carried 
out,  the  process  is,  in  addition,  reversed,  to  determine  the  small- 
est amount  of  complement  necessary  when  the  unit  of  amboceptor 
has  been  determined,  and  this  amount  of  complement  is  doubled 
before  using.  In  this  way  the  same  amounts,  quantitatively  speak- 
ing, of  amboceptor  and  complement  ar.e  used  for  each  test,  and 
lead  to  greater  accuracy. 

THE   AMBOCEPTOR. 

Furthermore,  the  fact  that  normal  human  sera  may  contain 
natural  amboceptor  for  sheep  corpuscles,  results  in  the  necessity 
of  testing  each  serum  to  be  examined  for  this  property.  If  hem- 
olysis follow  of  itself,  without  adding  specifically  prepared  anti- 
sheep  amboceptor,  in  the  presence  of  complement,  another  vari- 
ety of  sheep  corpuscle  must  be  used,  so  that  one  is  employed 
which  is  not  of  itself  hemolyzed.  This  leads  to  an  immense 
amount  of  work,  which  falls  away  when  the  Noguchi  system  is 
employed,  because  an  anti-human  amboceptor  and  human  cor- 
puscles are  employed.  The  serum  to  be  examined  can  be  readily 
inactivated  at  56°  C.  when  the  Noguchi  method  is  used.  At  first 
the  latter  recommended  the  use  of  the  fresh  active  serum  in 
smaller  amounts.     To-day  he  recommends  the  use  of  an  active 


BERGHAUSEN  49 

serum  when  antigen  prepared  by  the  acetone  method  of  purifi- 
cation is  employed. 

ANTIGEN. 

In  the  following  listed  cases,  antigen  prepared  both  from 
syphilitic  livers  and  normal  organs  was  employed,  as  alcoholic 
extracts.  No  essential  differences  were  found.  Noguchi's  method 
of  purifying  the  extract  by  means  of  acetone  is  an  excellent  one. 
By  this  means  objectionable  proteids,  which  may  of  themselves 
bind  complement,  are  disposed  of.  Furthermore,  an  uniformly 
pure  product  is  obtained  which  can  easily  be  preserved. 

THE  WASSERMANN  AND  NOGUCHI   METHODS. 

In  sixteen  cases  both  methods  were  simultaneously  employed. 
All  positive  cases  were  clinically  diagnosed  as  such.  The  one 
negative  tabetic  case  denied  previous  infection.  These  interpreta- 
tions were  made  by  me  in  an  unbiased  spirit,  since  much  depended 
upon  my  honesty  in  carrrying  out  the  work. 

The  following  table  shows  relative  merits  of  the  two  methods : 

Case  Wasser- 

No.       Clinical  Diagnosis.  Nogtichi.  mann. 

1  Normal    —  — 

2  Normal    —  — 

3  Normal    —  — 

4  Doubtful  previous  infection —  — 

5  Tertiary  lues -f  + 

6  Tertiary  lues +  — 

7  Tabes  dorsalis  -h  + 

8  Secondary  lues  under  treatment —  — 

9  Latent  lues   —  — 

10  Tertiary  lues -j-  + 

1 1  Tertiary  lues -f-  + 

12  Secondary  lues +  "i" 

13  Paralytic +  + 

14  Secondary  lues  under  treatment —  — 

15  Tabes  dorsalis  —  — 

16  Hereditary  lues  -f  + 

Total  number  of  cases  16;  Noguchi,  +  50  per  cent.,  —  50  per  cent; 
Wassermann,  -|-  43.8  per  cent.,  —  56.2  per  cent. 

Although  these  cases  are  relatively  few  in  number,  they  show 
us,  as  previous  observers  have  done,  the  greater  delicacy  of  the 
Noguchi  system.  Case  No.  6  was  undoubtedly  luetic,  and  not 
under  treatment  at  the  time,  and  yet  a  positive  reading  could  only 


50  D  A  N  D  R  I  D  G  E    MEMORIAL 

be  made  by  the  Noguchi  system.  A  negative  Noguchi  is  greater 
evidence  of  a  negative  luetic  condition  than  a  negative  Wasser- 
mann. 

THE   CLARK    METHOD. 

Clark  (Journal  of  Infectious  Diseases,  vol.  7,  No.  3,  May  20, 
1910)  has  descril^ed  a  simplification  of  the  Noguchi  system  in 
that  a  complete  reaction  is  completed  in  thirty  minutes,  and  the 
minimum  amount  of  complement  necessary  is  determined  and  used 
as  the  unit  of  complement  for  the  final  test.  In  four  cases  thus 
tested  the  results  vi^ere  identical  with  those  obtained  by  the  Nog- 
uchi method.  Outside  of  the  greater  rapidity  of  execution,  I 
could  see  no  advantage  over  the  Noguchi  system,  which  it  essen- 
tially is. 

THE    HECHT    METHOD. 

In  this  modification  we  need  only  the  patient's  serum,  a  sheep 
corpuscle  suspension  and  antigen.  It  is  dependent  upon  the  fact 
that  the  patient's  serum  may  contain  sufficient  natural  amboceptor 
for  sheep's  corpuscles.  In  the  few  tests  made  the  results  were 
unreliable,  and  therefore  the  method  was  no  longer  employed. 

THE   NOGUCHI   SYSTEM. 

In  the  following  table  are  listed  those  cases  which  were  clin- 
ically diagnosed  by  others,  and  by  subsequent  course  have  war- 
ranted me  in  making  such  a  classification.  Several  were  con- 
firmed by  autopsies  and  others  by  the  eflFect  of  treatment. 

No  of  r Noguchi n 

Cases.             Slage.  —  Percent.  -'-  Percent. 

2     Primary  2  100  0 

(2  weeks  and  3  weeks) 

7    Latent   3  43  4  57 

30    Secondary  2  6.6  28  93.4 

19    Tertiary    4  21  15  79 

23     Parasyphilitic 7  30.3  16  69.7 

4    Con«fenital  svphiiitics  ....  I  25  3  75 

50     Non-syphilitics     49  93  1  2 

Total  135 ;  iiegative  50.4  per  cent. ;  positive  50.6  per  cent. 

Comparing  the  results  obtained  in  the  second  table  with  those 
obtained  in  the  first  table,  we  see  the  constancy  of  results  ob- 
tained when  the  Noguehi  method  was  used.    Practically  one-half 


BERGHAUSEN  51 

of  all  cases  examined  were  positive  or  negative.  Although  the 
percentage  of  positive  cases  in  several  stages  is  not  quite  so  high 
as  given  by  other  observers,  to  one  acquainted  with  the  work  the 
slight  difference  is  easily  understood.  Clinicians  will  usually  in- 
sist on  their  being  correct  in  calling  one  case  positive,  another 
negative,  despite  the  laboratory  report;  especially  is  this  the  case 
in  obscure  lesions.  The  results  are  given  frankly  and  on  the 
basis  of  clinical  diagnosis  and  evidence. 

ITS  VALUE  TO  THE  INTERNIST. 

In  obscure  lesions  the  Wassermann  reaction  can  be  of  the 
greatest  assistance  to  the  clinician.  Plenty  of  evidence  is  at  hand 
to  prove  this  point,  but  I  do  not  wish  to  lengthen  this  report  by 
citing  case  histories.  In  liver  diseases  two  out  of  three  cases 
examined  were  decidedly  positive.  The  one  negative  case  was 
one  of  hypertrophic  cirrhosis.  In  heart  lesions  its  value  is  un- 
questioned at  times.  Past  observers  have  noticed  the  frequent 
pos'tive  findings  in  aortic  lesions  and  in  aneurism.  In  the  follow- 
ing table  are  given  results  obtained  in  a  few  cases.  The  clinical 
diagnosis  is  used  as  a  basis  for  the  correctness  of  my  work,  de- 
spile  the  fact  that  I  realize  that  in  no  other  branch  of  medicine 
do  clinicians  vary  so  much  at  times. 

No  of  I Noguchi  ^ 

Cases.  Lesion.  -j-         Per  cent.  —      Per  cent. 

8    Aortic   5  62.5  3  37.5 

1     Aneurism   ....  1  100 

3     Mitral    3  100 

1     Myocarditis  ....  1  100 

A  positive  Wassermann  would  confirm  a  clinical  diagnosis  of 
aor'itis;  a  negative  reaction  would  tend  more  to  a  mitral  lesion 
or  disease  of  the  heart  muscle  itself.  In  this  connection  it  is 
well  to  call  your  attention  to  the  possibility  of  a  number  of  lesions 
existing  at  the  same  time  in  one  individual.  A  patient  with  an 
old  mitral  lesion  on  a  rheumatic  basis  might  acquire  a  luetic  con- 
dition at  a  later  date.  Such  an  individual  might  give  a  positive 
syphilitic  reaction,  and  if  one  were  to  interpret  the  results  on  the 
basis  of  the  above  table,  confusion  would  at  once  arise.  A  Was- 
sermann reaction,  like  all  others  obtained  in  the  laboratory,  must 


52 


DANDRIDGE    MEMORIAL 


be   interpreted   only   after   thoroughly   considering  the  clinical 
findings. 

PARASYPHILITIC   CONDITIONS. 


No.  of 
Cases. 


Noguchi 


Per  cent. 
37.5 
25 

50* 


Clinical  Diagnosis.  -|-      P^r  cent. 

8    Tabes 5  62.5 

4  Cerebro-spinal  syphilis  ....  3  75 

2  Endarteritis  2  100 

3  Paresis  3  100 

2     Paralysis 1  50 

1     Idiocy  1  100 

Total  20:  positive  75  per  cent.*  Negative  25  per  cent. 

EFFECT  OF  TREATMENT. 

No.  Kind  of  Treatment.  Duration. 

1  Injection 3  weeks 

2  Injection 2  weeks 

3  Injection 2  weeks 

4  Infection a  few 

5  Injection a  few 

6  Injection 1  month 

7  Injection 5  months 

8  Combined 2  years 

9  Various many  years 

10  Various 4  years 

11  Internal 3  years 

12  Internal 3  years 

13  Injection 3  years 

14  Various 10  years 

15  Various 3  years 

16  Various (?) 


In  general,  the  more  prolonged  and  thorough  the  treatment, 
the  greater  the  tendency  towards  a  negative  reaction.  If  not  thor- 
oughly eradicated,  the  positive  reaction  may  develop  again  after 
the  lapse  of  many  months,  although  no  symptoms  may  be  pres- 
ent. At  times  a  distinctly  positive  reaction  may  shortly  become 
negative  under  thorough  treatment.  This  can  only  be  explained 
upon  the  basis  that  the  effect  is  greater  in  one  case  than  in  an- 
other, or  upon  the  assumption  that  the  original  infection  was  less 
intense. 

CONCLUSIONS. 

In  summing  up  this  work  the  following  conclusions  were 
reached : 

1.  A  positive  luetic  reaction  must  be  looked  upon  as  a  symptom 


Time  Elapsed.  K 

foguch 

+ 

+ 

-- 

-- 

5  months 

— 

4  weeks 

— 

6  weeks 

— 

6  months 

+ 

4  weeks 

4  weeks 

— 

4  weeks 

— 

9  months 

+ 

(?) 

7  months 



6  weeks 

— 

BERGHAUSEN  S3 

and  interpreted  as  such,  and  as  long  as  it  exists  the  patient  is  not 
free  from  the  danger  of  a  renewal  of  other  symptoms. 

2.  A  negative  reaction  does  not  necessarily  exclude  syphilis; 
it  would  tend  to  show  rhat  syphilis  is  either  absent  or  latent  as  far 
as  blood  serum  manifestations  are  concerned. 

3.  A  negative  Noguchi  is  greater  evidence  of  the  absence  of  an 
active  syphilis  than  a  negative  Wassermann. 

4.  A  positive  Wassermann  is  evidence  of  an  active  luetic  con- 
dition, when  frambesia,  leprosy  and  acute  scarlatina  (according 
to  others)  can  be  excluded. 

5.  A  distinctly  positive  Noguchi  has  the  same  value  as  a  posi- 
tive Wassermann. 

6.  A  slightly  positive  Noguchi  or  Wassermann  should  be  in- 
terpreted with  some  caution.  In  the  presence  of  a  positive  his- 
tory and  positive  findings  it  can  be  interpreted  in  a  positive  sense. 
In  doubtful  findings  it  should  be  repeated  in  two  weeks  for  a 
confirmation  of  the  results. 

7.  One  performing  the  serum  diagnosis  of  syphilis  should 
have  both  the  Noguchi  and  Wassermann  methods  at  his  disposal 
and  command.  The  Noguchi  method  gave  only  one  incorrect 
result  when  positively  reported,  taking  the  clinician's  word  as 
evidence  of  a  negative  luetic  condition,  although  the  case  had 
previously  been  treated  and  diagnosed  as  a  luetic  by  another  phy- 
sician. 


THE   SIGNIFICANCE  OF  EHRLICH'S  ALDEHYD 
.    REACTION  IN  THE  URINE.* 


BY  OSCAR  BERGHAUSEN,  A.B.,  M.D. 


About  eight  years  ago  Ehrlich  first  noticed  that  normal  urine 
gave  a  faintly  reddish  coloration  when  treated  with  a  muriatic 
acid  solution  of  paradimethyl-amino-benzaldehyd,  and  that  th's 
coloration  was  remarkably  intensified  in  certain  pathologic  condi- 
tions. To  Otto  Neubauer^  is  due  the  credit  of  having  isolated 
the  particular  chemical  substances  causing  the  reaction,  proving 
that  it  was  caused  by  pyrrol  derivatives  present  as  urobilinogen 
substances,  the  product  of  the  metabolism  of  blood  pigments ;  and 
reasoning  inversely,  he  came  to  the  conclusion  the  blood  pigments 
themselves  were  derived  from  pyrrol  derivatives  rather  than  indol 
substances,  as  upheld  by  Nenki.  He  furthermore  contended  that 
these  urobilinogen  substances,  mother  substances  from  which  the 
urobilin  was  formed,  were  present  in  increased  amounts  when 
there  was  an  increased  breaking  down  of  blood  pigments,  espe- 
cially in  malaria,  lead  colic,  lobar  pneumonia,  lung  infarct,  venous 
thrombosis,  liver  diseases  and  some  infectious  conditions. 

The  object  of  the  present  investigation  was  to  determine  the 
clinical  value  of  the  reaction,  since  it  is  so  readily  and  easily  car- 
ried out.  Undoubtedly  the  determination  of  the  urobilin  in  the 
urine  would  be  more  satisfactory,  as  recently  contended  by  Hil- 
debrandt,-  since  by  his  method  of  treating  the  urine  with  zinc  ace- 
tate all  urobilinogen  substances  are  converted  into  urobilin,  so 
that  both  substances  are  determined  at  once,  whereas  the  aldehyd 
reagent  shows  only  the  presence  of  urobilinogen,  its  action  on 
urobilin  causing  no  change  in  color.  The  present  investigation 
was  begun  some  nine  months  ago,  since  which  time  the  work  of 
Conner  and  Roper^  and  Hildebrandt^  has  appeared.    My  observa- 

*  Read  in  the  Section  on  Pathology  and  Physiology  of  the  American 
Medical  Association,  at  the  sixtieth  annual  session,  at  Atlantic  City,  June, 
1909,  and  published  in  the  Journal  of  the  American  Medical  Association, 
January  8,  1910,  vol.  liv,  pp.  99-103. 

55 


56  DANDRIDGE    MEMORIAL 

tions  so  clearly  verify  many  of  the  observations  and  predictions 
of  the  former  writers  that  their  publication  seems  unnecessary. 
The  question  of  the  origin  of  the  urobilinogen  and  urobilin 
naturally  is  brought  up,  and  the  various  theories  for  the  produc- 
tion of  the  same  called  to  mind,  namely,  the  enterogenous,  hepa- 
togenous, hematogenous,  histogenous  and  renal  theories,  recently 
so  well  summed  up  by  the  writers  referred  to.  At  the  outset  it 
may  be  stated  that  my  observations  would  tend  to  support  the 
enterohepatogenous  theory,  namely,  that  under  normal  conditions 
the  reduction  of  the  biliary  pigments  into  urobilinogen  and  uro- 
bilin takes  place  in  the  intestines,  in  accordance  with  the  views 
long  since  expressed  by  F.  Miiller  and  Otto  Neubauer,  and  that  a 
pathologic  urobilinuria  or  urobilinogenuria  results  when  the  liver 
is  insufficient;  that  is,  vv'hen  it  is  unable  to  excrete  an  increased 
amount  of  urobilinogen  or  urobilin  when  absorbed  from  the  intes- 
tines, or  when,  through  disturbances  in  the  liver  itself,  it  is  unable 
to  excrete  a  normal  or  even  deficient  amount  of  these  substances. 
In  infections  of  the  liver  evidence  would  point  to  the  fact  that 
these  substances  may  be  locally  formed  in  the  liver  itself.  Al- 
though the  histogenous  theory  cannot  be  discardeJ,  it  would  seem 
that  the  chief  organs  concerned  ordinarily  are  the  intestines  and 
the  liver. 

CLINICAL    APPLICATION. 

The  reagent  used  was  prepared  as  follows: 

Twenty  grams  of  paradimethyl  -amino-benzaldehyd  were  dis- 
solved in  1,000  c.c.  of  dilute  muriatic  acid,  made  by  diluting  150 
c.c.  of  the  chemically  pure  acid  to  1  liter  with  distilled  water.  To 
about  5  c.c.  of  cold  urine  taken  soon  after  being  voided,  because 
long  standing  causes  a  conversion  of  the  urobilinogen  into  uro- 
bilin through  the  action  of  air  and  sunlight,  5  to  10  drops  of  the 
reagent  were  added.  The  mixture  was  shaken  and  allowed  to 
stand  a  minute  or  two.  Normal  urine  gave  a  varying  coloration, 
which  was  intensified  to  a  distinct  cherry-red  color  on  heating, 
usually  associated  with  a  peculiar  pungent  odor.  Neubauer  as- 
serts that  the  urobilinogen  represents  various  substances,  ranging 
in  structure  from  CgHijN  (hemopyrrol)  to  C30H40N4O7  (uro- 
bilin itself),  and  that  the  more  sensitive  give  the  reaction  in  the 


B  E  R  G  H  A  U  S  E  N  57 

cold,  the  less  sensitive  only  on  heating.  When  the  reaction  is 
distinctly  scarlet  in  the  cold,  a  pathologic  condition  of  the  urine 
is  present.  Experiment  soon  showed  that  the  intensity  of  the 
reaction  varied,  even  in  the  normal  urine,  and  the  following 
scheme  of  recording  results  was  adopted: 

A  negative  result,  i.e.,  maintenance  of  the  original  color  of 
the  urine,  or  a  yellowish  coloration  after  adding  the  reagent  was 
reported  as  — 0;  a  faint  reddish  color  only  obtained  on  looking 
through  the  whole  columns  of  urine  in  the  test-tube  from  above, 
as  -j-  1 ;  when  the  mixture  presented  a  pinkish  or  faintly  reddish 
hue,  on  looking  at  it  from  in  front,  as  -[-  2 ;  when  a  distinctly  scar- 
let coloration  was  obtained  it  was  recorded  as  -{-2,  which  intensity 
of  reaction  alone  is  of  any  pathologic  significance. 

Examination  of  my  own  urine  through  a  period  of  twenty-five 
days  showed  that  the  reaction  varied  from  one  day  to  the  other, 
but  that  it  never  assumed  a  -}-3  reaction  in  the  cold,  but  always 
on  heating.  From  this  it  was  assumed  that  an  apparently  normal 
individual,  with  a  properly  functionating  liver,  was  able  to  pre- 
serve a  urobilinogen  balance ;  that  is,  the  liver  was  able  to  ex- 
crete these  substances  derived  from  the  intestines,  only  allowing 
a  trace  to  appear  in  the  urine.  It  may  be  possible  that  in  cases 
of  severe  constipation,  or  so-called  torpid  liver,  even  in  an  appar- 
ently normal  individual,  the  reaction  might  approach  -f-3  in  in- 
tensity, but  if  this  condition  persists  following  free  purgation, 
undoubtedly  a  pathologic  condition  is  at  hand. 

The  reaction  was  next  applied  to  the  urine  of  a  series  of  nearly 
200  cases  taken  from  all  wards  of  the  City  Hospital.  The  tables 
show  the  distinct  degree  of  reaction  obtained  in  many  of  these 
cases.  First,  as  to  the  color  of  the  urine,  this  was  recorded  in  a 
total  number  of  107  cases.  Of  the  74  light-colored  urines  ex- 
amined, 

13  (17.5  per  cent.)  reacted  +3 

9  (12.4  per  cent.)  reacted  +2 

10  (13  5  per  cent.)  reacted  -"-l 

42  (56.6  per  cent.)  reacted  — 0 

Of  the  33  cases  of  dark-colored  urine  examined, 

13  <'39.4  per  cent.)  reacted  -j-3 

5  (15.1  per  cent.)  reacted  -"-2 

2  (  6.1  per  cent.)  reacted  -f-1 

13  (39.4  per  cent.)  reacted  —0 


58 


DAN BRIDGE    MEMORIAL 


This  shows  conclusively  that  the  positive  reaction  was  more 
commonly  found  in  dark-colored  urines,  21.9  per  cent,  more  than 
in  light-colored  urines,  but  that  it  also  occurred  quite  frequently 
in  the  latter.  In  the  dark-colored  urines  a  negative  reaction  was 
correspondingly  less  frequent — 17.2  per  cent.  less.  On  the  whole, 
then,  the  reaction  is  independent  of  the  color  of  the  urine,  being 
more  common,  however,  in  dark-colored  urines. 


TABLE  SHOWING  DEGREE  OF  REACTION  IN  ABOUT  ONE  HUNDRED 
AND    FIFTY    HOSPITAL    CASES. 


No. 
Clinical   Diagnosis.  Cases. 

Acute  lobar  pneumonia   17 

Malaria  2 

Acute  articular  rheumatism 12 

Scarlet  fever   5 

Typhoid  fever   10 

Influenza   5 

Erysipelas   2 

Simple  pulmonary  tuberculosis 5 

Complicated  pulmonary  tuberculosis 2 

Appendicitis   3 

Pelvic  cellulitis   2 

Tonsilitis  2 

Pus  tubes   4 

Endometritis    1 

Cystitis  2 

Cirrhosis  of  liver  2 

Carcinoma  of  liver 1 

Miliary  abscess  of  liver  1 

Catarrhal  jaundice  4 

Myocardial  insufficiency  plus  edema 8 

Pleurisy  with  effusion 5 

Pericarditis  plus  diaphragmiatic  pleurisy....  2 

Pleurisy,  dry  adhesive 3 

Acute  nephritis   5 

Uremia  1 

Chronic  nephritis   5 

Abortion  3 

Shot  wound  of  chest 1 

Shot  wound  of  abdomen  1 

Shot  wound  of  kidney   1 

Ruptured  abdominal  aneurism 1 

Fracture  of  femur  1 

Hemorrhoids   2 

Venous  thrombosis 1 

Syphilis  2 

Lead  colic  1 

Trichiniasis   2 

Diabetes  mellitus 5 

Chronic  alcoholism 2 

Carbolic  acid  poisoning 1 


+3 
7 
2 
5 


Reaction 


+2 

2 


1 


— 0 
6 

5 
5 
5 
2 
2 
3 


BERGHAUSEN  59 

No.     I Reaction  > 

Clinical    Diagnosis.  Cases.  +3     -f-2    -\-\     — 0 

Diabetes  insipidus  2         .         .         .         2 

Burn  cases   4         .         .         .         4 

Morphinism 3        1         .         .         2 

Senile  dementia 1         .  .  .         1 

Dementia  paralytica 1 

Neurasthenia   2 

Melancholia  1 

Acute  gastritis  1 

Acute  bronchitis   4 

To  sum  up :  The  reaction  is  most  commonly  obtained  in  diseases 
of  the  liver,  myocardial  insufficiency  with  edema,  pleurisy  with 
effusion,  and  acute  catarrhal  jaundice,  all  conditions  in  which  the 
proper  elimination  of  the  urobilinogen  through  the  liver  after  ab- 
sorption from  the  intestines  is  interfered  with;  furthermore,  in 
some  infectious  conditions,  as  lobar  pneumonia,  malaria  and  artic- 
ular rheumatism.  An  absence  of  a  pathologic  reaction  has  been 
conspicuous  in  more  or  less  localized  septic  states,  as  pelvic  ab- 
scess, pus  tubes,  tonsillitis,  simple  pulmonary  tuberculosis,  acute 
bronchitis,  erysipelas,  dry  pleurisy  and  pericarditis,  despite  the 
increased  temperature. 

In  this  series  of  cases  the  absence  of  the  reaction  in  typhoid 
fever  and  scarlet  fever  is  to  be  noted.  In  localized  extravasations 
of  blood  following  shot  wounds,  or  rupture  of  aneurism,  no  in- 
crease in  the  intensity  of  the  reaction  is  to  be  noticed.  Con- 
valescence from  a  condition  in  which  the  reaction  was  marked 
was  followed  by  a  return  to  the  normal ;  thus,  in  both  cases 
of  malaria  the  quick  response  to  quinine  treatment  was  followed 
by  a  disappearance  of  the  reaction.  In  incipient  cases  of  dis- 
turbed myocardial  insufficiency,  and  in  suspected  cases  of  gall- 
stone trouble  with  a  clear  history  and  response  to  treatment,  the 
reaction  was  not  present.  Undoubtedly  a  positive  reaction  which 
persists,  in  these  cases,  would  indicate  a  marked  disturbance  either 
in  the  production  of  the  urobilinogen  in  the  small  intestines  plus 
increased  absorption  or  a  disturbance  in  the  eliminating  power  of 
the  liver.  It  must  be  borne  in  mind  that  one  section  of  the  liver 
may  be  involved  and  yet  the  remainder  ma}'  be  efficient,  as  was 
demonstrated  in  one  severe  case  of  syphilitic  cirrhosis  of  the 
liver,  in  which  the  reaction  was  negative,  though  a  diminished 
formation  in  the  intestine  may  have  been  present.     The  reaction 


60  DANDRIDGE    MEMORIAL 

is  not  a  constant  one,  even  in  those  conditions  most  commonly 
the  cause.  That  a  positive  reaction  may  be  of  some  assistance  in 
suspected  liver  involvement  was  shown  in  a  case  of  miliary  ab- 
scess of  the  liver  following  infectious  thrombophlebitis. 

Case  I. — The  patient,  a  young  man,  first  showed  symptoms  of 
appendicitis ;  later  localized  peritonitis  developed,  at  which  time 
the  reaction  was  +2  in  intensity.  These  symptoms  subsided,  but 
later  increased  temperature  plus  tenderness  over  the  gall-bladder 
my  tie  the  attending  physicians  suspect  gall-bladder  or  liver  in- 
volvement. The  urine  showed  a  positive  aldehyd  leaction  in  cold 
and  the  presence  of  leucin  and  tyrosin  in  the  urine.  Operation 
was  resorted  to  for  suspected  cholecystitis.  At  operation  the  gall- 
bladder was  apparently  normal  and  cultures  taken  proved  nega- 
tive.    The  patient  collapsed  suddenly  on  the  table. 

Autopsy. — This  revealed  an  enlarged  liver,  studded  through- 
out with  miliary  abscesses,  along  the  portal  tract  evidently,  and 
an  infectious  thrombophlebitis.  Cultures  from  the  portal  vein 
and  abscess  areas  both  showed  the  presence  of  diplococci  and  a 
colon-like  organism,  evidently  the  result  of  infection  following 
absorption  from  the  originally  involved  appendix. 

Clinically  this  case  beautifully  demonstrates  what  Fischler* 
showed  experimentally  on  animals,  namely,  that  under  certain 
conditions  urobilin  can  be  formed  in  the  liver  itself.  He  made 
biliary  fistulas  in  dogs,  draining  the  bile  to  the  outside,  and  then 
injected  amyl  alcohol  and  phosphorus  into  the  gall-bladder.  The 
liver  became  involved,  and  urobilin  again  appeared  in  the  urine; 
with  the  subsidence  of  the  condition  it  again  disappeared.  In  my 
case  the  liver  itself  became  involved  through  infection  along  the 
portal  tract. 

EXPERIMENTAL   DATA. 

Since  Muller  reported  the  interesting  fact  that  when  the  com- 
mon bile  duct  becomes  occluded  the  urobilin  disappears  from  the 
urine,  the  German  school  has  adhered  to  the  enterogenous  theory 
as  to  the  origin  of  the  urobilin,  namely,  that  when  the  bile  is 
poured  into  the  intestines  and  is  subjected  to  the  action  of  the  re- 
ducing bacteria,  urobilin  is  formed  and  absorbed  from  the  intes- 
tines ;  it  is  again  excreted  through  the  bile  and  to  some  extent 
through  the  urine.  Bile  usually  contains  some  urobilin.  Neu- 
bauer^  later  asserted  that  occlusion  of  the  common  duct  would 
also  be  followed  by  absence  of  the  urobilinogen  in  the  urine,  bile 


BERGHAUSEN  61 

and  intestines,  and  that  this  might  be  shown  by  a  negative  aldehyd 
reaction  in  the  urine,  both  in  the  heat  and  cold.  Kimura^  showed 
that  normal  bile  always  contained  urobilinogen,  using  the  aldehyd 
reaction  and  the  spectroscope  to  detect  the  absorption  band. 

With  the  object  of  verifying  this  fact  through  animal  experi- 
ment, the  following  investigations  were  made :  It  was  found  that 
normal  rabbit  urine  reacted  toward  the  aldehyd  reagent  exactly  as 
does  the  normal  human  urine.  Rabbits  were  therefore  used,  and 
each  experiment  conducted  under  ether  anesthesia.  Ether  was 
given  in  minimal  amounts,  and  never  exceeded  thirty  minutes. 
In  two  instances  the  animals  died  within  a  few  hours  following 
the  operation,  but  no  changes  beyond  the  normal  were  found  in 
the  urine. 

ExPERiMEXT  I. — Male  rabbit.  The  common  bile  duct  was 
ligated  with  silk  and  the  operation  wound  closed.  The  animal 
died  eighteen  hours  after  operation. 

Urinalysis. — Urine  before  operation  negative  in  the  cold,  -j-3 
on  heating.  After  operating,  the  urine  taken  from  the  bladder 
soon  after  death  was  reddish.  Aldehyd  reagent  caused  a  nega- 
tive reaction  in  the  cold,  the  reddish  color  of  the  original  urine 
soon  disappearing  on  adding  the  reagent.  On  heating,  a  brown- 
ish precipitate  formed,  but  no  scarlet  color  developed.  The  cold 
urine  was  then  heated,  filtered,  and  the  reagent  added  after  cool- 
ing. Reaction  was  +1 ;  on  heating  no  increase  in  the  intensity 
of  the  reaction.  The  urine  drawn  before  operation  and  preserved 
on  ice  in  the  dark,  when  added  to  the  catheterized  specimen  im- 
mediately caused  a  scarlet  coloration  on  heating  with  the  reagent. 

Autopsy. — This,  made  about  twelve  hours  after  death,  showed 
abdominal  wound  perfect,  no  escape  of  bile,  liver  enlarged,  con- 
gested, apparently  bile-stained.  Common  duct  ligated,  severe 
congestion  from  this  point  unward.  The  aldehyd  reaction  nega- 
tive in  the  heat  and  cold,  but  not  confirmed  by  spectroscope  ex- 
amination. Kidneys  both  showed  an  acutely  congested  appear- 
ance. 

Experiment  II. — ]\Iale  rabbit;  common  duct  ligated  and  op- 
eration wound  closed.  The  animal  died  thirty-six  hours  after 
operation. 

Urinalysis. — Urine  after  operation  showed  a  negative  reaction 
in  the  cold  and  -f-l  on  heating.  Addition  of  the  urine  obtained 
on  the  previous  day  before  operation  caused  intense  reddish  color- 
ation on  heating  with  the  reagent. 

Autopsy. — Thoracic  organs  normal.  Abdomen  showed  an  early 


62  DANDRIDGE    MEMORIAL 

localized  peritonitis  immediately  below  the  operating  wound.  Liver 
was  bile-colored,  gall-bladder  dilated. 

These  experiments  both  show^  that  occlusion  of  the  common 
duct  is  early  manifested  by  a  decided  alteration  in  the  normal 
reaction.  On  heating  with  the  reagent  only  the  faintest  trace  of 
a  reddish  color  was  noticed.  On  adding  the  normal  urine,  how- 
ever, the  color  immediately  became  scarlet,  showing  conclusively 
the  urobilinogen  had  practically  been  eliminated ;  in  reality  none 
had  been  formed,  because  the  action  of  the  reducing  bacteria  in 
the  intestines  had  been  excluded.  The  fact  that  the  reaction  on 
heating  was  still  recorded  as  +1  would  show  that,  as  late  as 
thirty-six  hours  after  the  second  experiment  there  was  still  a 
slight  trace  of  urobilinogen  present,  which  no  doubt  was  due  to 
residual  urobilinogen  of  the  tissues,  rhis  time  interval  not  being 
sufficient  to  cause  complete  elimination  from  the  system.  Several 
experiments  were  made  of  infecting  the  gall-bladder  above  the 
point  of  constriction  in  order  to  observe,  if  possible,  the  reoccur- 
rence of  the  scarlet  color  due  to  changes  in  the  liver  through  bac- 
terial action.     No  results  were  obtained,  however. 

Complete  occlusion  of  the  common  bile-duct  is  therefore  fol- 
lowed by  a  negative  reaction,  both  in  the  cold  and  in  the  heat, 
after  adding  the  aldehyd  reagent  to  the  urine.  There  immediately 
occurs  to  one  the  possibility  of  using  this  fact  as  a  means  of  diag- 
nosis in  cases  of  total  obstruction  of  the  duct  through  a  stone, 
through  inflammatory  changes  in  the  mucosa,  or  by  compression 
from  without  through  any  source.  Are  these  the  only  conditions 
which  can  cause  this  change  in  the  reaction?  Kimura^  has  shown 
that  in  severe  diarrheas  a  similar  condition  is  obtained,  owing 
to  the  fact  probably  that  no  bile  can  be  reduced  in  the  intestines 
under  such  a  condition,  or  absorption  becomes  impossible.  We 
must  further  conceive  of  the  possibility  of  a  patent  ductus  veno- 
sus,  allowing  of  the  discharge  of  bilirubin  in  the  intestines,  al- 
though occlusion  of  the  duct  be  present.  In  the  newly  born  the 
same  condition  is  obtained,  because  bacterial  reduction  has  not 
as  yet  begun. 

In  my  list  of  clinical  cases  two  other  conditions  were  encoun- 
tered which  gave  a  similar  result: 

Case  II. — Infant,  female,  aged  seventeen  months,  died  eight 
days  after  acute  phosphorus  poisoning  caused  by  eating  matches. 


BERGHAUSEN  63 

The  urine  examined  before  death  had  unfortunately  been  stand- 
ing from  thirty  to  thirty-six  hours  before  the  aldehyd  reaction  was 
tried.  It  was^  however,  found  negative  both  in  the  heat  and  the 
cold.    Tyrosin  was  also  found  in  the  urine. 

Autopsy,  made  about  four  hours  after  death,  shov/ed  a  some- 
what enlarged  liver,  distinctly  fatty.  Heart  showed  beginning 
endocarditis.  Intestines  were  somewhat  congested.  Microscopic 
examination  of  the  liver  showed  distinct  fatty  changes  and  round- 
celled  infiltration  about  the  vessels;  the  hver  cells  were  poorly 
stained  and  fat  globules  numerous.  The  urine  obtained  at  au- 
topsy showed  a  negative  aldehyd  reaction  both  in  the  heat  and 
the  cold. 

Case  III. — Clinical  diagnosis,  transverse  myelitis.  An  opera- 
tion had  been  performed  to  relieve  any  supposed  compression 
of  the  cord  about  at  a  level  with  the  fifth  dorsal  vertebra,  since 
a  distinct  traumatic  history  was  given.  No  relief  followed.  Im- 
mediate operation,  however,  was  successful  from  a  technical 
standpoint.  The  patient  sank  rapidly  from  incontinence  of  both 
urine  and  feces,  and  at  last  refused  to  eat,  so  that  exhaustion  ul- 
timately resulted  in  death.  For  several  days  previous  to  death 
profuse  hemorrhages  occurred  from  the  lower  bowel. 

Autopsy. — There  was  found  an  extremely  fatty  liver,  chronic 
inters" "tial" nephritis,  and  hemorrhagic  condition  of  the  lower 
colon.  The  urine  obtained  at  this  time  likewise  showed  a  nega- 
tive reaction  in  the  heat  and  cold. 

In  both  tt  ese  cases  it  may  be  argued  that  post-mortem  changes 
in  the  urine  caused  these  variations  in  the  aldehyd  reaction  from 
the  normal.  Among  numerous  cases  examined  after  death,  how- 
ever, these  two  cases  were  the  only  ones  which  presented  such  a 
condition.  Hiidebrandt  believes  that  in  severe  phosphorus  poison- 
ing the  general  destruction  of  the  liver  would  lead  to  such  find- 
ings. He  has  no  direct  evidence  to  support  his  views,  however. 
Case  II  was  undoubtedly  one  of  acute  phosphorus  poisoning,  and 
tyrosin  was  found  in  the  urine ;  bile  could  not  be  detected  by  nitric 
acid  or  iodine  tests  Before  death,  however,  the  stools  were  very 
frequent,  quite  pale,  and  grayish  in  color.  To  what  extent  the 
profuse  diarrhea  was  instrumental  in  causing  the  negative  uro- 
bilinogen reaction  cannot  be  definitely  told.  Likewise  in  Case  III 
frequent  diarrheic  stools  were  present  before  death,  and  in  addi- 
tion a  severe  hemorrhage  from  the  bowel  on  repeated  occasions. 
In  both  cases,  however,  the  liver  showed  marked  fatty  degenera- 
tion, which  would  tend  to  support  the  views  of  Hiidebrandt.    In 


64  DANDRIDGE    MEMORIAL 

the  future  severe  anemias  may  be  shown  to  react  in  a  similar  way, 
because  of  the  lessened  destruction  of  blood  pigment  in  late  stages. 

In  phosphorus  poisoning  the  variety,  whether  acute  or  chronic, 
must  also  be  taken  into  consideration.  Harnack"  has  recently 
shown  experimentally  that  in  acute  cases  following  injection  of 
phosphorus  into  the  stomach  rapid  degeneration  and  fatty  changes 
are  produced  in  the  liver.  In  more  chronic  cases,  as  when  sub- 
cutaneous injections  of  phosphorus  in  oil  are  given,  the  degenera- 
tive changes  in  the  liver  are  still  present,  but  not  so  intense  as  in 
the  more  acute  cases,  inflammatory  reactions  on  the  part  of  the 
liver  being  more  common.  Therefore,  it  may  be  possible  that  in 
chronic  phosphorus  poisoning  the  destruction  to  the  liver  sub- 
stance may  not  be  so  intense  as  to  lead  to  a  total  absence  of  uro- 
bilinogen in  the  urine,  as  indicated  by  a  negative  aldehyd  reaction 
in  the  heat  and  cold. 

The  animal  experiment  was  again  called  into  play,  to  shed,  if 
possible,  some  light  on  this  subject. 

Experiment  III. — A  male  rabbit  was  given  phosphorus  in  oil 
mixed  with  the  food.  About  six  hours  later  it  began  to  show 
signs  of  being  ill,  and  died  some  time  during  the  night. 

Urinalysis. — Before  operation,  at  which  time  the  bladder  was 
emptied,  the  urine  showed  a  negative  reaction  in  the  cold,  and  a 
positive  reaction  on  heatinaf.  The  urine,  withdrawn  from  the 
bladder  some  time  after  death,  showed  a  similar  reaction. 

Autopsy. — Stomach  full  of  food,  phosphorus  fumes  still  es- 
caping. The  most  dependent  part  of  the  organ  showed  an  escha- 
rotic-like  condition  of  the  mucosa.  The  liver  was  not  particularly 
enlarged,  was  distinctly  mottled  on  section,  but  did  not  present  a 
fatty  appearance.  Microscopically  the  liver  showed  distinct 
cloudy  swelling  of  the  cells,  round-celled  infiltration  about  the 
vessels,  and  engorgement  of  the  capillaries.  No  fatty  globules 
could  be  detected.  The  kidneys  were  enlarged  and  had  a  con- 
gested appearance. 

The  above  experiment  did  not  result  in  such  marked  fatty 
changes  as  to  lead  to  a  complete  obliteration  of  the  urobilinogen 
in  the  urine.  It  is  possible  that  the  death  occurred  too  rapidly  for 
such  changes  to  be  caused,  and  that  a  more  gradually  induced 
toxemia  would  have  produced  the  desired  result.  To  establish 
this  point  a  second  animal  was  used  for  experiment. 

Experiment  IV. — A  male  rabbit  was  given  phosphorus  in  oil 
per  mouth.    On  the  three  succeeding  days  the  urine  was  normal 


BERGHAUSEN  65 

in  reaction,  i.  e.,  negative  in  the  cold  and  positive  on  heating.  On 
the  fourth  day  more  phosphorus  was  fed.  On  the  day  following 
the  reaction  was  -f-  "^  i"  the  cold,  distinctly  positive.  This  per- 
sisted for  five  days,  when  more  phosphorus  was  given  per  mouth. 
On  the  following  day  the  reaction  was  negative  in  the  cold,  and  a 
brownish  coloration  only  developed  on  heating.  Twenty-four 
hours  later  the  reaction  was  negative  in  the  heat  and  cold.  The 
animal  now  showed  signs  of  considerable  weakness  and  suffering, 
and  was  killed  by  chloroform. 

Autopsy. — The  liver  was  somev/hat  contracted,  pale  yellow, 
with  a  mottled  appearance  on  section.  The  liver  was  still  firm. 
Microscopically  there  was  almost  total  obliteration  of  the  liver 
cells;  those  remaining  were  pale  with  poorly  stained  nuclei. 
Numerous  fat  molecules  were  distributed  throughout.  There  was 
round-celled  infiltration  about  the  vessels,  and  seemingly  a  begin- 
ning formation  of  connective  tissue.  The  stomach  was  full  of 
undigested  food.  The  small  intestines  were  nearly  empty,  the 
large  intestines  packed  with  ordinarily  formed  stools.  The  bile 
was  thin,  light  greenish  in  color,  and  showed  a  negative  aldehyd 
reaction  in  the  cold  and  in  the  heat. 

In  this  instance  the  destruction  of  the  liver  substance  had 
been  so  great  that  no  bilirubin  was  offered  to  the  intestines  for 
reduction.  All  stages  of  the  reaction  were  also  beautifully  demon- 
strated, varying  from  the  normal  to  a  relatively  and  at  last  an 
absolutely  deficient  liver,  as  indicated  on  successive  days  by  the 
changes  in  the  aldehyd  reaction. 

CONCLUSIONS. 

The  clinical  value  of  the  aldehyd  reaction  obtained  by  adding 
the  reagent  to  cold,  freshly  passed  urine,  and  then  noticing  the 
changes  in  the  color,  at  first  in  the  cold  and  then  on  heating,  is 
manifest,  though  limited  at  times. 

The  color  reaction  in  the  cold  is  of  pathologic  significance  only 
when  a  distinct  scarlet  color  is  obtained. 

When  the  reaction  persists  following  free  purgation  a  patho- 
logic condition  is  at  hand. 

The  reaction  is  most  commonly  present  in  disea.ses  of  the  liver 
and  bile  passages,  severe  grades  of  myocardial  insufficiency,  and 
certain  infectious  conditions,  as  lobar  pneumonia  and  malaria. 

The  reaction  is  not  a  constant  one,  even  in  apparently  severe 
grades  of  the  above  conditions,  presumably  because  the  liver  is 


66  DANDRIDGE     MEMORIAL 

still  efficient  in  excreting  any  normal  or  increased  amount  of  uro- 
bilinogen offered  it. 

Localized  infections  are  more  seldom  accompanied  by  this  re- 
action, and  when  it  does  persist  in  such  conditions  the  condition 
of  the  intestines  and  liver  should  be  taken  into  consideration. 

In  early  grades  of  myocardial  insufficiency  of  gall-stone 
trouble,  and  of  liver  disturbances  the  reaction  is  often  a  negative 
one.  The  appearance  of  the  reaction  in  such  cases  previously 
negative  would  arouse  suspicions  of  disturbances  in  the  hepatic 
function;  inversely,  the  disappearance  of  a  reaction  previously 
positive  would  indicate  improvement. 

The  positive  reaction  is  not  constant  in  localized  extravasa- 
tions of  blood  into  the  tissues. 

When  the  reaction  is  positive  some  care  must  be  exercised  in 
the  selection  of  an  anesthetic  for  operations,  since  it  is  well  known 
that  chloroform,  for  instance,  can  be  a  direct  liver  poison. 

The  absence  of  the  reaction,  both  in  the  heat  and  in  the  cold, 
would  indicate  obstruction  in  the  flow  of  bile  into  the  intestines. 

This  condition  is  also  obtained  in  cases  of  severe  diarrhea,  in 
the  newly  born,  and  in  severe  grades  of  destruction  of  the  liver 
substance. 

In  conclusion  I  wish  to  express  my  indebtedness  to  the  medical 
and  surgical  staff  officers  of  the  City  Hospital  for  their  kind  per- 
mission in  allowing  me  to  use  the  material  at  hand,  to  the  internes 
— more  particularly  Drs.  Light,  Schlanser,  Monroe  and  Mussey 
— also  to  Dr.  A.  E.  Osmond,  without  whose  kind  assistance  and 
skill  much  of  the  experimental  work  would  have  been  impossible. 

REFERENCES. 

1.  Neubaner,  Otto :  Sitzungsh.  d.  Gcsellsch.  f.  Morphol.  u.  Physiol,  in 
Miinchen,  1903.  No.  2,  xix,  32. 

2.  Hildebrandt:  Milnch.  mcd.  Wochcnsch.,  April  6.  1909,  p.  710. 

3.  Conner,  L.  A.,  and  Roper,  J.  C. :  Arch.  Int.  Merf.,  Jan.  15,  1909,  ii,532. 

4.  Fischler :  Das  Urobilin  u.  seine  klinische  Bedeutung.  Thesis,  Heidel- 
berg, 1906. 

5.  Kimura,  T. :  Deutsch.  Arch.  f.  klin.  Med.,  1904,  Ixxix,  274. 

6.  Harnack,  E. :  Milnch.  mcd.  Woch.,  March  2,  1909,  p.  436. 


IMPETIGO  CONTAGIOSA  TRANSMITTED  BY 
MACHINE  OIL.* 


BY  OTTO  V.    HUFFMAN,    M.D., 


A  BRIEF  HISTORY  of  an  epidemic  of  impetigo  contagiosa  among 
the  machinists  of  a  local  manufactory  is  of  interest  because  it 
brings  forth  some  facts  not  obtainable  from  individual  personal 
histories  and  shows  the  necessity  of  investigating  infectious  dis- 
eases in  a  comprehensive  way,  and  of  enforcing  sanitary  pre- 
cautions in  machine  shops.  As  long  as  these  patients  were  treated 
by  their  several  physicians,  a  variety  of  diagnoses  were  made 
without  discovering  the  cause  of  the  disease. 

In  March,  1909,  quite  a  number  of  the  machinists  working  in 
the  screw  machine  department  complained  that  the  oil  which  they 
were  using  caused  a  rash  where  it  came  in  contact  with  the  skin. 
The  company  sent  a  specimen  of  the  oil  to  the  laboratory  to  be 
examined.  It  was  found  that  the  oil  did  not  contain  any  chemical 
impurities,  that  it  was  neither  acid  nor  alkaline.  It  did  not  seem 
necessary  to  look  into  the  matter  of  organic  impurities,  as  the  oil 
was  made  from  lard  which  during  the  process  of  rendering  was 
heated  to  a  sufficient  degree  to  make  it  sterile. 

Upon  receiving  the  report  that  the  cause  of  the  rash  com- 
plained of  by  their  men  could  not  be  found  in  the  oil  as  purchased, 
the  company  ordered  the  complaining  men  to  report  for  examin- 
ation and  treatment  and  to  bring  some  of  the  oil  actually  used  by 
them. 

Quite  a  number  had  complained,  but  only  six  reported.  Of 
these  six  machinists,  five  presented  inflamed  papules  and  pustules 
distributed  irregularly  over  the  upper  extremities,  face,  and  neck, 
wherever  the  oil  might  reach  the  exposed  skin.  The  sixth  man 
did  not  have  a  rash,  but  said  that  he  had  had  a  "felon"  on  his 
thumb  which  was  entirely  healed.  Upon  questioning  him,  he 
stated  that  he  had  worked  at  a  screw  machine  supplied  by  the 
same  oil  pump  as  that  which  supplied  oil  to  the  machines  and 

*  Reprinted  from  the  New  York  Medical  Journal,  December  31,  1910. 

67 


68  DANDRIDGE     MEMORIAL 

lathes  of  the  other  five  men;  that  he  had  worked  in  the  oil  while 
the  abscess  on  his  thumb  was  discharging  pus ;  that  this  occurred 
just  before  the  rash  appeared  upon  his  fellow  workmen;  that  he 
had  not  had  any  rash  but  thought  perhaps  that  his  abscess  might 
have  been  due  to  the  oil. 

This  verbal  evidence  needed  only  to  be  supplemented  with 
knowledge  of  the  lubricating  system  of  these  six  machines  to 
point  clearly  to  the  fact  that  the  pyogenic  germs  discharged  into 
the  oil  from  the  abscess  on  the  finger  of  this  man  had  been  the 
cause  of  the  pustular  rash  on  the  other  five.  At  the  factory  it 
was  found  that  the  waste  oil  of  the  six  machines  at  which  these 
men  had  worked  drained  to  a  common  reservoir  from  which  after 
being  strained  it  was  again  pumped  to  the  same  six  machines — 
thus  making  successive  cycles.  The  identical  oil  which  had  been 
at  one  time  in  contact  with  the  abscess  had  been  mixed  with  all 
the  oil  in  the  reservoir  and  thus  diluted  had  been  splashed  upon 
the  arms  and  faces  of  the  machinists. 

The  men  with  the  rash  were  cleaned  first  with  tincture  of 
green  soap,  applied  with  pledgets  of  cotton  so  as  not  to  cause 
scratches  or  points  of  inoculation,  then  with  alcohol  to  further 
help  dissolve  the  oil  which  might  be  absorbed  carrying  the  pyo- 
genic germs  beneath  the  skin  in  the  same  way  as  plague  bacilli 
may  be  inoculated  by  inunction.  The  parts  were  then  gently 
dried  and  dressed  in  ammoniated  mercurial  ointment  held  by 
gauze  bandages.  The  men  were  kept  from  work  and  made  un- 
eventful recoveries. 

It  is  interesting  to  note  that,  although  the  man  who  had  had 
the  abscess  on  his  finger  continued  to  work  in  the  oil  laden  with 
pyogenic  germs,  he  did  not  develop  a  rash.  He  had  evidently 
acquired  an  immunity  to  the  pyogenic  germs  of  his  own  pus. 

As  it  was  clear  that  the  oil  pumped  to  the  six  machines  was 
laden  with  pus  germs  which  caused  the  pustular  rash,  it  was 
recommended  to  the  company  to  destroy  or  sterilize  it.  Further 
inquiry  in  regard  to  other  complainants  showed  that  a  few  who 
had  worked  temporarily  at  some  of  these  machines  had  slight 
rashes  and  that  others  presented  skin  diseases  which  in  no  way 
could  be  attributed  to  the  oil.  The  company  destroyed  the  oil  and 
has  had  no  trouble  since. 


OSTEOCHONDRITIS  DISSECANS:    CONCERNING  ITS 

NATURE  AND  RELATION  TO  FORMATION 

OF  JOINT  MICE.* 


BY  ALBERT  H.  FREIBERG,  M.D.,  AND  PAUL  G.  WOOLLEY^  M.D. 


The  formation  of  loose  bodies  is  one  of  the  most  interesting 
phenomena  to  be  observed  in  connection  with  the  pathology  of 
the  chronic  joint  diseases.  Long  known  as  an  accompaniment 
of  certain  cases  of  arthritis  deformans,  it  was  also  believed  that 
corpora  mobilia  were  frequently  the  result  of  traumata.  In  1887, 
Koenig  described  the  formation  of  these  bodies  by  a  process 
which  he  considered  sui  generis  and  which  he  named  accordingly, 
osteochondritis  dissecans.  Unable  to  satisfy  himself  either  by 
experiment  on  the  cadaver,  or  as  the  result  of  a  large  experience, 
of  the  relationship  between  trauma  and  the  production  of  joint 
mice,  he  felt  constrained  to  describe  as  osteochondritis  dissecans, 
a  definite  and  distinct  joint  affection,  not  associated  with  arthritis 
deformans  nor  in  his  judgment  related  to  it ;  nor  yet  standing  in 
any  demonstrable  connection  with  trauma.  As  the  result  of  a 
process  whose  nature  was  not  clear  to  him,  Koenig  described  the 
separation  from  the  underlying  joint  ends  of  pieces  of  varying 
size.  These  fragments  acquire  a  covering  of  connective  tissue 
containing  some  cartilage  cells.  Usually  one  is  able  to  find  the 
defect  in  the  joint  segment  from  which  the  separation  occurred 
although  this  rapidly  fills  in  with  cartilage.  According  to  Koenig 
also,  these  joints  are  otherwise  normal  excepting  some  effusion 
and  villous  hypertrophy  and  after  the  removal  of  the  foreign 
bodies  they  remain  well.  It  must  not  be  overlooked  that  the 
formation  of  loose  bodies  in  certain  cases  by  the  chondrification 
or  ossification  of  hypertrophied  joint  villi  is  accepted  by  Koenig 
also. 

In  1896,  Barth  disputed  the  existence  of  osteochondritis  dis- 
secans as  a  distinct  process,  urging  that  for  chondral  and  osteo- 

*  Read  before  the  American  Orthopedic  Association  at  its  twenty-fourth 
annual  meeting,  held  in  Washington,  May  3-5,  1910,  and  published  in  the 
American  Journal  of  Orthopedic  Surgery,  February,  1911. 

69 


70  DANDRIDGE     MEMORIAL 

chondral  loose  bodies  only  two  modes  of  formation  could  be 
accepted;  namely,  arthritis  deformans  and  trauma.  According 
to  Earth  pathologic-anatomic  proof  of  the  existence  of  osteo- 
chondritis was  lacking;  Koenig's  clinical  and  operative  observa- 
tion was  of  doubtful  value  and  his  explanation  was  purely 
hypothetical. 

In  1908,  Ludloff  described  two  knee  cases  in  which  the  diag- 
nosis of  osteochondritis  dissecans  was  made  on  the  basis  of  the 
radiogram  and  confirmed  by  operation;  in  both  cases  the  radio- 
gram showed  a  body  about  the  size  of  a  date  seed  which  had 
apparently  separated  from  the  internal  condyle  of  the  femur 
opposite  the  insertion  of  the  posterior  crucial  ligament.  It  ap- 
peared to  lie  in  a  cavity  hollowed  out  of  the  condyle.  In  his  first 
case  the  cartilage  was  intact  over  the  body  and  it  was  liberated 
only  by  incision;  in  his  second  case  a  part  of  the  bone  fragment 
had  already  separated  as  a  "corpus  liberum."  In  this  case  the 
other  and  supposedly  normal  knee  presented  a  similar  condition 
in  the  radiogram.  Most  of  the  cases  of  osteochondritis  dissecans 
of  the  knee  which  have  been  reported  have  similarly  concerned 
this  particular  part  of  the  internal  condyle  and  Ludloft  seeks  to 
harmonize  the  divergent  views  of  Koenig  and  Earth  by  a  study 
of  the  vascular  arrangement  of  this  neighborhood.  The  arteria 
genu  media  ramifies  over  the  posterior  crucial  ligament  toward 
the  lateral  edge  of  the  internal  condyle.  It  is  here  a  terminal 
vessel  and  would  appear  to  be  susceptible  of  injury  at  this  point 
by  forced  simultaneous  hyperextension  and  inward  rotation  of 
the  joint.  The  circulation  being  thus  cut  oft"  at  this  point  we 
should  then  have  following  an  osteochondritis  dissecans  of 
traumatic  origin.  It  is,  however,  significant  in  our  judgment, 
that  in  Ludloff's  Case  II  both  knees  were  affected  and  that  in 
neither  of  his  cases  was  the  history  of  trauma  forthcoming. 

Our  interest  in  this  subject  was  aroused  by  the  following 
clinical  observation : 

A  Russian  girl  twenty  years  of  age  was  admitted  into  hospital 
because  of  trouble  with  both  knees.  She  had  been  having  pain 
and  frequent  joint  locking  since  her  childhood,  both  knees  being 
affected  in  like  degree.  At  the  age  of  seventeen  an  arthrotomy 
of  both  knees  was  done  in  Russia  and  loose  bodies  were  removed, 


FREIBERG     AND     W  O  O  L  L  E  Y  71 

which  were  afterwards  shown  to  her.  A  second  operation  be- 
came necessary  because  of  the  appearance  of  more  loose  bodies. 
No  radiograms  were  made  in  Russia  by  her  surgeons.  These 
operations  afforded  her  reHef.  She  asserts  that  at  no  time  had 
she  any  injury  to  the  knees  of  noteworthy  character.  She  is  of 
decidedly  nervous  temperament,  but  seems  otherwise  in  good 
general  health ;  is  of  short  stature  but  well  developed  and  de- 
cidedly plump. 

Upon  admission  she  complained  of  pain  in  walking,  but  es- 
pecially in  standing.  The  right  knee  was  much  more  troublesome 
than  the  left.  Has  had  no  attacks  of  joint  locking  since  the  last 
operation.  Both  knees  appeared  swollen  to  some  extent  and  both 
had  about  normal  mobility.  Some  tenderness  on  palpation  of  the 
joint  line  on  the  mesial  surface  of  both  knees,  much  more  marked 
in  the  right  side.  No  muscular  atrophy.  No  crepitation  or  grating 
on  motion  of  either  joint.  Palpation  disclosed  no  abnormality  in 
the  contours  of  the  joint  segments.  Radiograms  were  now  made 
by  Dr.  Lange. 

DESCRIPTION  OF  X-EAYS. 

Right  Knee. 

(a)  Antero-Posterior  View. — The  most  striking  feature  of 
this  view  is  the  appearance  of  the  internal  condyle  of  the  femur, 
We  see  here  an  apparent  defect  in  the  bone  3  cm.  long,  in  which 
lie  two  fragments  which  are  respectively  1  cm.  by  0.3  cm.  wide 
and  0.3  cm.  long  by  0.4  cm.  wide.  The  defect  in  the  femur  gives 
the  appearance  of  two  cavities  corresponding  in  size  and  shape 
to  the  two  fragments  which  lie  in  them.  The  fragments  appear 
to  be  completely  separated  from  the  surface  of  the  bone  beneath 
them.  Superimposed  upon  the  shadow  of  the  fragment  of  the 
fibular  side  and  to  a  slight  degree  upon  the  end  of  the  internal 
one  also,  is  seen  the  lighter  shadow  of  a  third  mass  of  oval  shape, 
measuring  1.6  x  1.3  cm.  The  upper  border  of  this  shadow  is  in 
great  part  obscured  by  the  dense  shadow  of  the  femur  upon  which 
it  is  superimposed.  The  joint  space  itself  seems  of  about  normal 
width,  and  the  tibia  and  femur  appear  to  be  of  normal  density. 
One  must  be  struck  with  the  fact,  however,  that  at  the  joint  line, 
and  especially  as  concerns  its  mesial  half,  both  the  femur  and 


'^l  t>A^JDRIDGE    MEMORIAL 

tibia  differ  from  the  normal  in  contour.  The  inter  condyloid  emi- 
nence of  the  tibia  projects  upward  much  less  than  usual,  and  the 
intercondyloid  fossa  of  the  femur  is  correspondingly  shallow. 
The  contour  of  the  internal  condyle  of  the  femur  lacks  its  usual 
convexity,  being  almost  straight;  the  internal  articular  facet  of 
the  tibia  is  correspondingly  shallow.  There  is  but  slight  indica- 
tion of  the  marginal  bone  proliferation  commonly  seen  in  arthritis 
deformans. 

Since  the  most  marked  changes  to  be  seen  in  the  antero-pos- 
terior  view  are  found  in  the  internal  condyle,  it  is  unfortunate 
that  the  lateral  view  only  is  accessible,  since  no  plate  was  made 
before  operation  with  the  mesial  side  of  the  joint  applied.  For 
this  reason  the  mesial  condyle  is  but  imperfectly  portrayed  and 
the  view  of  the  pathological  condition  here  is  very  unsatisfac- 
tory. In  this  view  of  the  knee,  however,  it  may  be  observed  that 
at  the  upper  margin  of  the  patella  near  the  posterior  surface, 
there  is  a  blunt,  bony  outgrowth,  and  in  front  of  this  apparently 
a  loose  body  of  bony  texture  lying  in  the  tendon  of  the  quad- 
riceps. 

Mesial  View  of  the  Right  Knee  (made  since  operation). — On 
March  25,  1910,  a  mesial  view  of  the  right  knee  was  obtained. 
In  this  view  it  may  be  seen  that  the  shell  of  bone  which  has  sep- 
arated from  the  internal  condyle  is  of  greater  extent,  in  an 
antero-posterior  sense,  than  might  have  been  imagined;  it  com- 
prises about  the  posterior  three-fifths  of  the  condyle. 

Left  Knee. 

The  same  views  were  obtained  of  this  joint. 

(a)  Antero-Posterior  View. — The  general  contours  of  the 
bones  are  very  similar  to  those  of  the  right  knee.  The  anterior 
border  of  the  internal  condyle  of  the  femur  appears  to  be  over- 
hanging. It  gives  the  impression  that  it  was  probably  at  one  time 
the  seat  of  a  condition  like  that  of  the  right  knee,  and  that  a 
considerable  amount  of  repair  had  taken  place.  The  condyle  has 
not  only  lost  its  convexity  below,  but  has  apparently  lost  some 
of  its  bulk  in  a  vertical  sense.  A  loose  body  appears  at  the  mesial 
side  of  the  internal  epicondyle. 

(b)  Lateral  View. — The  loose  body  just  mentioned  is  now 


FREIBERG     AND     WOOLLEY  73 

seen  to  "be  behind  the  internal  condyle.  (It  was  not  seen  at  the 
operation.)  The  patella  presents  a  blunt,  thick  outgrowth  from 
its  upper  and  posterior  margin.  There  is  a  suggestion  of  lipping 
to  be  seen  at  the  anterior  margin  of  the  upper  end  of  the  tibia. 

Operation,  January  19,  1910. 

By  incision  at  the  mesial  side  of  the  patella,  the  right  knee 
was  opened.  There  was  unusually  great  venous  hemorrhage  from 
the  capsule.  The  arthrotoniy  was  done  upon  the  previously  flexed 
knee,  as  suggested  by  Robert  Jones.  A  loose  body,  the  size  of 
a  cherry  was  at  once  seen,  attached  to  the  internal  condyle  by  a 
slender  pedicle  composed  apparently  of  connective  tissue  and 
synovial  membrane.  This  was  easily  removed,  but  to  our  sur- 
prise nothing  was  to  be  seen  of  the  two  fragments  shown  in  the 
radiogram,  nor  of  the  defect  in  the  internal  condyle,  although  the 
exposure  of  the  joint  was  thoroughly  satisfactory.  After  care- 
ful inspection  the  cartilage  over  the  mesial  condyle  appeared  of 
different  color  than  elsewhere,  and  pressure  upon  it  seemed  to 
indicate  that  it  was  loosened  from  the  underlying  bone.  A  small 
incision  showed  this  to  be  the  case.  Unaware  of  Ludloflf's  ex- 
perience, related  above,  it  was  deemed  unwise  to  further  disturb 
the  cartilage.  The  synovial  membrane  of  the  joint  appeared 
thickened,  and  two  nodular  masses  were  excised  and  preserved, 
one  from  the  tibia  and  one  from  the  femur. 

An  arthrotomy  of  the  left  knee  was  now  done  through  a  small 
incision.  No  loose  body  was  seen.  The  mesial  condyle  of  the 
femur  appeared  unusually  flat  and  somewhat  irregular  in  surface, 
but  covered  with  cartilage  of  normal  appearance.  Here,  too, 
the  synovial  membrane  was  thickened  and  a  nodule  was  excised 
from  the  margin  of  the  tibial  surface 

Prompt  healing  occurred.  The  patient  soon  left  the  hospital, 
and  has  since  been  at  work  with  practically  no  disturbance  of 
joint  function  and  no  pain. 

The  case  just  reported  assumes  a  greater  interest  for  two  rea- 
sons. The  first  of  these  is  that  thus  far  few  cases  corresponding 
to  Koenig's  osteochondritis  have  been  reported  in  which  a  radio- 
graphic study  has  been  made.  While  the  radiographic  aspect  of 
the  right  knee  made  it  appear  typical  of  this  disease,  it  differs 
radically  from  this  in  the  reappearance  of  symptoms  after  the 


74  D  A  N  D  R  I  D  G  E     MEMORIAL 

removal  of  the  loose  bodies;  indeed  this  joint  affection  would 
seem  to  have  assumed  a  distinctly  progressive  character,  whereas 
this  has  not  been  true  of  the  cases  reported  by  Koenig  and  oth- 
ers- This  would  appear  to  strengthen  Earth's  view,  that  we  are 
dealing  here  with  arthritis  deformans,  and  especially  so  since 
there  is  in  both  knees  evidence  of  new  bone  formation  at  the 
margins  of  the  patella.    On  the  other  hand  it  must  be  noted: 

1.  That  at  the  operation  no  degeneration  of  the  joint  cartilage 
was  to  be  seen. 

2.  That  although  the  disease  has  been  in  existence  for  a  num- 
ber of  years,  only  the  slightest  marginal  proliferation  is  to  be 
seen  in  either  femur  or  tibia. 

3.  That  while  arthritis  deformans  has  been  carefully  studied 
radiographically,  lamellar  separation  of  bone  from  the  surface 
of  the  condyles,  such  as  we  here  observe,  has  thus  far  not  been 
described  as  a  part  of  otherwise  characteristic  instances  of  this 
disease. 

While  the  above  considerations  pertain  to  the  clinical  and 
radiographic  aspects  of  this  case,  it  must  be  here  observed  that 
since  the  work  of  Nichols  and  Richardson,  and  especially  since 
the  appearance  of  Wollenborg's  paper  on  the  etiology  of  arthritis 
deformans,  our  clinical  and  radiographic  concepts  of  arthritis 
deformans  require  to  be  greatly  modified  and  brought  anew  into 
correspondence  with  anatomical  processes  which  have  been  clearly 
established.  We  must  therefore  seek  reply  to  the  following  ques- 
tions : 

(a)  Are  we  in  this  case  dealing  with  two  distinct  joint  diseases, 
or  simply  with  different  manifestations  of  a  single  joint  affection? 

(b)  Are  all  of  the  changes  in  this  patient's  joints  to  be  recon- 
ciled with  the  modern  conception  of  arthritis  deformans? 

(c)  Are  we  dealing  with  the  osteochondritis  dissecans  of 
Koenig,  and  is  this  process  incompatible  with  a  rational  notion 
of  arthritis  deformans? 

It  appears  to  us  that  for  the  answer  to  these  important  ques- 
tions recourse  must  be  had  to  the  microscopic  investigation  of 
the  specimens  removed  from  our  patient. 

We  had  at  our  disposal  for  microscopic  examination  four 
pieces  of  tissue;  three  of  these,  a  pedunculated  body  and  two 


FREIBERG    AND     WOOLLEY  75 

synovial  tags,  were  from  the  right  knee  joint,  and  one,  a  bit  of 
tissue  resembling  cartilage  and  synovial  membrane,  from  the  left 
knee  joint. 

The  pedunculated  body  was  a  rounded  mass,  measuring  15  x 
12  X  8  mm.,  elastic,  of  pearly  appearance,  and  apparently  composed 
of  cartilage  or  dense  connective  tissue,  or  both,  and  possibly  some 
bone.  At  one  end  was  a  short  fibrous  tag  of  not  more  than  1.5 
mm.  diameter,  that  represented  the  pedicle.  This  body  was  di- 
vided longitudinally,  and  since  there  was  a  feeling  of  grating 
during  division,  both  halves  were,  after  fixation  in  formalin, 
placed  in  the  phloroglucin-nitric  acid  mixture  to  insure  decalcifi- 
cation. The  tissue  from  the  left  knee  was  also  decalcified.  The 
other  tissues  were  fixed  in  formalin.  All  the  specimens  were 
finally  embedded  in  celloidin,  and  after  cutting  were  stained  with 
hematoxylin  and  eosin. 

Sections  of  the  large  body  showed  that  it  was  composed  of  a 
central  area  containing  lime  salts  in  small  amount  and  a  small 
amount  of  yellowish  material  that  resembles  the  remains  of 
blood  pigment.  The  tissue  about  the  central  area  was  hemoge- 
nous  and  hyaline,  and  contained  groups  of  cartilage  cells.  In 
the  neighborhood  of  the  central  area  such  groups  were  sparsely 
distributed,  but  near  the  periphery,  which  was  composed  of  hya- 
line fibrous  tissue,  they  were  more  numerous.  The  fibrous  tissue 
of  the  periphery  was  continuous  with  the  pedicle. 

Each  of  the  two  bits  of  synovial  tissue  showed  the  same  struc- 
ture; that  is  to  say  they  were  composed  of  rather  villous  clumps 
of  connective  tissue  and  were  richly  supplied  with  blood  ves- 
sels. Our'  interest  at  once  centered  upon  these  vessels,  for  almost 
without  exception  ~they  showed  well-marked  signs  of  perithelial 
and  endothelial  hyperplasia.  In  some  cases  they  were  surrounded 
by  abundant  collections  of  small  round  cells.  In  others  they  were 
either  partially  or  completely  obliterated  by  endothelial  over- 
growth. In  the  villi  in  which  the  thelial  proliferation  was  most 
marked  the  perivascular  connective  tissue  was  more  hyaline  than 
in  those  in  which  the  vessels  were  of  more  normal  appearance. 

The  tissue  from  the  left  knee  appeared  almost  avascular,  and 
was  composed  chiefly  of  a  fibro-cartilaginpus  tissue,  the  fibrous 
elements  predominating.     In  this  tissue  two  villi  were  evident  in 


76  DAN  BRIDGE     MEMORIAL 

sections,  and  these  were  composed  of  fibrous  tissue,  with  a  few 
attenuated  nuclei,  arranged  for  the  most  part  near  the  periphery, 
and  also  with  well-formed  cartilage  corpuscles.  In  such  villi  there 
were  also  a  few  cells  of  indeterminate  character,  resembling 
fibroblastic  elements,  and  which  from  their  situation  and  arrange- 
ment might  possibly  represent  the  vestiges  of  vanished  blood- 
vessels. 

The  evidence  gathered  in  the  examination  of  these  tissues 
which  were  removed  at  operation,  is  in  support  of  the  conception 
that  the  production  of  the  large  pedunculated  body,  which  was 
to  all  intents  a  free  body,  was  the  result  of  changes  in  the  syno- 
vial membranes,  which  were  the  result  of  blood  vascular  prolif- 
eration and  obliteration.  This  process  corresponds  with  that 
suggested  by  Wollenberg  as  the  foundation  for  the  production 
of  arthritis  deformans.  Upon  this  basis  we  may  logically,  we 
think,  account  for  some,  at  least,  of  the  free  bodies  removed  from 
the  joints  of  our  patient.  The  question  remains,  however,  as  to 
whether  the  deep  shadows  in  the  radiograms  call  for  any  other 
explanation;  whether,  for  instance,  the  flatness  of  the  articular 
surfaces  has  played  an  important  role  in  the  production  of  the 
general  condition  in  the  joints,  as  Preiser  suggests;  whether  the 
condition  is  one  of  osteochondritis  dissecans,  as  Koenig  con- 
ceived it. 

It  seems  to  us  that  Preiser's  theory  of  static  imperfections 
cannot  explain  all  the  trouble,  because  it  cannot  explain  the  pres- 
ence of  free  bodies  at  points  where  static  forces  do  not  act.  Fur- 
ther, because  the  whole  process  as  we  have  studied  it  seems  to 
be  correlated  in  all  its  aspects  and  progressive,  we  think  it  more 
reasonable  to  apply  one  principle,  if  it  is  possible,  both  in  the  pro- 
duction of  articular  deformities  and  in  osteochondritis  dissecans. 

We  found  in  our  case  a  body  attached  by  a  pedicle  and  com- 
posed of  cartilage,  and  with  some  evidence  of  calcification,  but 
with  no  actual  bone,  and  moreover  with  the  area  of  calcification 
at  the  center  of  the  body.  We  found  no  depression  in  the  bone, 
either  at  operation  or  in  the  radiograms,  that  would  account  for 
so  large  a  loss  of  substance  as  required  by  the  size  of  the  pedun- 
culated body.  But  we  did  find  in  radiograms  two  areas  in  the 
internal  condyle  of  the  right  femur  that  seem  to  point  to  the  in- 


FREIBERG    AND     WOOLLEY  17 

cipient  freeing  of  two  fragments  of  cartilage.  These  areas  do 
not  correspond  to  the  position  they  should  occupy  to  satisfy  the 
demands  of  Ludloff.  It  seems  to  us  that  the  whole  condition 
may  be  explained  upon  the  basis  of  the  vascular  theory  of  Wol- 
lenberg,  and  that  the  changes  in  the  joints  which  we  have  de- 
scribed are  in  perfect  accord  with  the  modern  conception  of  ar- 
thritis deformans  as  outlined  by  Nichols  and  Richardson,  and 
finally  that  vascular  changes  may  also  account  for  osteochondritis 
dissecans. 

It  seems  unnecessary  to  describe  the  vascular  process  at  great 
length,  for  Wollenberg's  article  is  exhaustive.  We  shall  then 
merely  outline  it  as  follows:  As  the  result  of  one  of  a  number  of 
possible  causes  acting  chiefly  upon  the  joint  tissues,  chronic  vas- 
cular changes  are  produced.  Among  such  causes  might  well  be 
static  imperfections,  traumata,  acute  or  chronic  of  other  sorts, 
toxins  circulating  in  the  blood,  local  disorders  of  metabolism,  or 
chronic  infections.  Infarction  would  not  produce  the  effects, 
because  those  which  we  are  studying  are  of  gradual  development. 
It  is  possible,  however,  that  infarction  might  produce  bodies  of 
the  nature  of  those  described  by  Koenig,  as  being  covered  on  one 
side  by  joint  cartilage  and  on  the  other  by  bone.  At  any  rate, 
whatever  the  cause,  whether  chronic  congestion  or  chronic  mild 
irritation,  the  result  would  be  changes  in  the  vessel  walls,  endar- 
teritis or  periarteritis  or  both,  and  these  eventually  would  lead  to 
local  interference  with  nutrition.  Gradually  interference  with 
the  nutrition  of  bone  tends  to  produce  metaplasia  with  formation 
of  tissue  that  is  capable  of  depending  less  directly  upon  a  blood 
supply.  Cartilage  is  such  a  tissue.  When  finally  obliteration  of 
the  vessels  is  complete,  necrosis  will  occur,  and  the  line  of  necro- 
sis will  appear  at  the  place  where  the  cartilage  is  no  longer  able 
to  obtain  nourishment,  either  by  absorption  from  the  joint  cavity 
or  from  collateral  blood-vessels.  The  tendency  would  therefore 
be  not  to  form  free  bodies,  but  only  partially  free  ones,  which 
being  held  in  place  by  the  living  joint  cartilage,  might  again 
unite  as  collateral  vessels  developed,  or  which  might  become  free 
as  the  result  of  trauma.  Such  free  bodies  would  be  rounded,  oval 
or.  flat,  from  the  fact  of  their  gradual  formation,  and  because 


78  D  A  N  D  R  I  D  G  E     M  E  ^I  O  R  I  A  L 

of  the  tendency  to  compensation  on  the  part  of  collateral  vessels, 
and  not  wedge-shaped  as  in  infarction. 

In  the  case  of  the  process  in  the  synovial  membrane  the  same 
conception  holds.  With  chronic  irritation  of  toxic  or  mechanical 
origin  there  is  congestion  and  even  proliferation  of  blood-vessels, 
with  hyperplasia  of  the  synovia  and  formation  of  villi.  As  the 
irritation  continues  to  act,  obliterative  vascular  changes  gradually 
reduce  the  blood  supply;  the  connective  tissue  becomes  hyaline 
and  later  chondrified  and  even  calcified,  and  later  atrophy  of  the 
pedicles  results  in  free  bodies. 

Upon  the  basis  of  such  changes  we  may  conceive  that  the 
conformation  of  the  joint  surfaces  becomes  altered  to  such  an 
extent  that  static  variations,  friction  and  chronic  hyperemia  may 
form  a  circulus  vitiosus,  and  that  as  a  result,  at  one  time  or  an- 
other, varying  with  blood  supply,  we  have  the  production  of  ec- 
chondroses  and  other  progressive  or  regressive  changes  that 
eventually  bring  about  the  more  marked  changes  which  we  clas- 
sify under  the  head  of  arthritis  deformans. 

In  our  judgment,  Wollenberg's  paper  constitutes  one  of  the 
most  important  contributions  which  has  been  made  to  the  study 
of  the  chronic  deforming  disease  of  the  joints.  By  his  theory  of 
vascular  change  there  can  be  explained  those  mixed  forms  of 
joint  affection  in  which  we  find  evidences  of  both  the  prolifera- 
tive and  degenerative  types  of  joint  disease.  If,  instead  of  in- 
volving the  cartilage  and  synovial  membrane,  the  vascular  change 
takes  place  in  bone  near  the  articular  surface,  and  where  the  vas- 
cular supply  approaches  the  "terminal"  variety,  it  may  result  in 
that  local  sequestration  of  bone  with  its  overlying  cartilage,  which 
has  by  Koenig  been  called  osteochondritis  dissecans. 

To  us  the  great  interest  in  our  case  lies  in  the  fact  that  the 
three  varieties  of  joint  changes  may  be  found  going  on  in  the 
same  joint  at  one  time,  apparently  dependent  in  their  reciprocal 
relations  upon  the  vascular  changes,  as  they  vary  either  in  their 
location  in  bone  or  synovial  membrane,  or  as  they  vary  in  the 
degree  to  which  they  have  progressed.  In  view  of  this  study, 
we  must  concur  with  Nichols  and  Richardson  in  holding  that  the 
types  of  chronic  deforming  joint  affections  cannot  be  looked 
uf>on  as  separate  and  distinct  diseases.     We  must  look  to  the 


FREIBERG     AND     WOOLLEY  79 

future  to  disclose  the  etiological  factors  which  determine  the 
predominance  of  this  or  that  type  in  a  given  case.  It  would 
appear  that  the  first  stage  in  such  etiological  study  has  been 
reached  with  a  recognition  of  the  role  which  is  played  by  the 
vascular  changes. 

DISCUSSION. 

Dr.  C.  F.  Painter,  of  Boston,  opening  the  discussion  on  the 
paper  of  Drs.  Freiberg  and  Woolley,  said  that  what  had  inter- 
ested him  particularly  in  this  paper  was  the  demonstration  of 
the  lesions  in  the  radiograms.  If  he  had  understood  Dr.  Frei- 
berg correctly,  he  had  attempted  to  make  these  comparable  to 
the  appearance  in  the  radiogram  of  the  lesions  that  occur  in  the 
chronic  form  of  arthritis  deformans,  or  osteoarthritis,  or  hyper- 
trophic arthritis  (according  to  the  term  selected  by  the  one  con- 
sidering the  subject).  It  did  not  seem  to  Dr.  Painter  that  these 
radiograms,  as  they  were  representative  of  the  pathology  of  the 
condition,  were  suggestive  of  the  appearances  in  the  ordinary 
cases  of  chronic  hypertrophic  osteoarthritis.  The  explanation, 
as  indicated  by  the  specimen  removed  at  operation,  might  have 
been  that  these  were  the  result  of  vascular  changes  present  at 
the  same  time;  but  that  these  changes  were  comparable  to  the 
hypertrophic  form,  which  might  or  might  not  have  been  caused 
by  the  vascular  changes,  did  not  seem  to  Dr.  Painter  to  have  been 
demonstrated. 

Dr.  Woolley,  closing  the  discussion,  said  that  he  had  not  very 
much  more  to  say  on  this  subject,  having  said  about  all  he  could 
think  of  while  writing  the  paper  with  Dr.  Freiberg.  He  did  not 
think  that  they  had  proved  anything  by  the  small  amount  of  work 
that  they  had  done,  but  he  did  think  that  they  had  some  basis 
for  supporting  the  work  of  Wollenberg.  The  examination  of  a 
few  tags  of  synovial  membrane,  even  though  they  did  show  the 
ciianges  described,  was  not  enough  upon  which  to  build  an  hy- 
pothesis. It  was  interesting  that  they  could  get  these  various 
changes  in  this  one  case — changes  that  appeared  like  those  de- 
scribed by  other  men  in  various  forms  of  atrophic  and  hypertro- 
phic joint  disease. 

Dr.  Freiberg,  closing,  said  that  he  must  agree  entirely  with 
Dr.  Painter  in  stating  that  the  appearances  of  the  radiogram  in 
this  case  were  unlike  the  appearances  in  cases  cf  hypertrophic 
arthritis.  He  had  not  meant  to  convey  the  impression  that  they 
were  like  the  appearances  usually  seen  in  radiograms  of  hyper- 
trophic arthritis.  The  interesting  point  was  that  they  had  a  case 
in  which  free  bodies  had  formed  and  were  apparently  still  form- 
ing, as  in  the  right  knee,  and  in  which  a  second  kind  of  free 


$0  DANDRIDGE     MEMORIAL 

bodies  had  apparently  formed  on  other  occasions,  one  of  which 
was  apparently  about  to  be  set  free  (the  cherry-like  body  that 
was  removed  from  the  right  knee).  When  they  came  to  examine 
the  changed  synovial  membrane  of  these  joints,  they  found 
chronic  changes  in  accordance  with  the  changes  described  by 
Wollenberg  in  cases  that  were  typical  of  hypertrophic  arthritis, 
as  seen  clinically  and  in  the  radiogram ;  and  it  seemed  to  them 
that  these  two  things  must  be  brought  into  correlation,  and  that 
some  explanation  of  this  character  was  to  be  found  for  these 
cases  in  the  osteochondritis  dissecans  of  Koenig.  He  thought  it 
was  really  an  example  of  a  variant  of  the  same  basic  process 
which  gives  various  clinical  pictures  of  chronic  joint  disease. 

REFERENCES. 

Koenig:  Deutsche  Zeitschrift  f.  Chir.,  1888,  Bd.  xxvii. 
Earth:  Verh.  d.  Deut.  Gesell.  f.  Chir.,  1896. 

Ludloff:  Arch.  f.  klin.  Chir.,  Bd.  Ixxxvii,  1908;  also  Ceniralbl.  f.  Chir., 
1908. 

Preiser :  Verhandl.  d.  Gesell.  Dent.  Naiurforsch,  1898,  xi,  p.  199. 

Nichols  and  Richardson:  Journal  of  Med.  Research. 

Wollenberg:  Deut.  Zeihchr.  f.  Orthop.  Chir.,  1909,  Bd.  xxiv,  p.  359. 


A  DESCRIPTION  OF  FOUR  FILARIA  LOA 
FROM  THE  SAME  PATIENT.* 


BY   O.   V.    HUFFMANN,    M.D.,   AND   WM.    B.    WHERRY,    M.D. 


A  COMPARISON  of  the  descriptions  of  the  morphological  character- 
istics o/  Filaria  loa  by  previous  authors  shows  differences  which 
are  explained  by  the  study  of  our  uninjured  specimens.  We 
have  prepared  a  table  (q.v.)  which  shows  the  results  of  the  work 
of  various  observers,  together  with  our  own.  We  believe  that 
most  of  the  drawings  so  far  published  are  somewhat  misleading; 
we  have  therefore  drawn  the  essential  parts  as  seen  through  the 
microscope  with  an  entire  diameter  and  a  portion  of  a  longi- 
tudinal section  in  focus.  The  drawings  are  not  composite  or 
schematic,  but  have  been  made  on  a  large  scale,  with  accuracy 
in  the  measurements,  so  as  to  represent  the  different  parts  in 
proper  proportion. 

This  species  of  nematode  was  first  described  in  1777  as  be- 
ing diiTerent  from  the  guinea-worm  by  Guyot,  a  French  naval 
surgeon,  after  he  had  made  several  voyages  to  the  coast  of  An- 
gola. He  noted  that  these  worms  were  very  white,  harder  and 
shorter  than  the  guinea-worm. 

A  number  of  cases  of  the  removal  of  worms  from  the  eyes 
of  negroes  in  St.  Domingo,  Cayenne  and  South  America  were 
reported,  but  it  was  not  until  1838  that  the  next  identification  of 
this  species  was  made,  when  Guyon  described  -i  Filaria  which 
had  been  removed  from  the  eye  of  a  negress  on  the  island  of 
Martinique  and  sent  to  him.  He  also,  in  1864,  described  part  of 
a  worm  removed  from  the  eye  of  a  negro  in  Gaboon.  In  1877 
Morton,  of  Philadelphia,  published  an  account  of  a  loa  removed 
from  the  eye  of  a  native  of  Gaboon,  with  a  brief  description  of 
the  worm  by  Leidy.  The  specimen  had  dried  in  transit.  In  this 
account  we  also  find  the  first  record  of  infections  in  Caucasians. 
Bachelor  (1879),  of  Gaboon,  extracted  a  specimen  from  the  eye 
of  a  native  and  sent  it  perfectly  preserved  to  the  United  States. 

*  From  Parasitology,  vol.  iv,  No.  1,  March,  1911. 

81 


82  D  A  N  D  R  1  D  G  E     MEMORIAL 

Leukart^  (1886)  identified  the  species  as  distinct  from  the  guinea- 
worm;  he  had  received  a  female  41  mm.  long. 

In  1895  Manson"  described  a  male  Filcria  loa  removed  from 
the  eyelid  of  an  Englishman  who  had  been  in  West  Africa;  he 
also  described  a  male  and  female  removed  from  the  eye  of  an 
English  lady  who  had  been  in  Old  Calabar.  In  the  same  year 
Ludwig  described  a  female  specimen  removed  from  the  eye  of  a 
Russian  who  had  been  in  Fernando  Po,  Gaboon,  Kamerun  and 
the  Gold  Coast.  The  specimen  had  been  injured  in  several 
places.  Blanchard  (1899)  gave  an  extended  account  of  the 
anatomy  of  a  male  and  female  removed  from  the  same  host,  who 
had  been  in  the  French  Congo;  these  worms  were  quite  young. 
In  1901  Annett,  Dutton  and  Elliott  obtained  a  female  Filaria  loa 
at  Bonney,  but  they  did  not  report  in  regard  to  the  host  nor  from 
what  part  of  the  body  it  was  obtained.  In  1903  two  males  and 
two  females,  sent  from  Nigeria,  were  briefly  described  by  Ozzard- 
Looss'"'  (1904)  published  a  complete  anatomical  description  of  two 
specimens  which  had  been  sent  to  him  from  the  Gold  Coast  and 
labeled  Filaria  loa  without  other  data.  The  male  was  very 
slightly  injured  by  forceps  just  behind  the  cephalic  end.  Ward* 
(1906)  noted  some  points  which  he  considered  peculiar  to  the 
three  males  studied  by  him  and  referred  to  the  admirable  account 
of  Looss  for  a  complete  description  of  their  structure.  One  of 
his  specimens  had  been  sent  to  him  mounted  in  balsam.  This 
author  gives  a  most  complete  critical  bibliography  en  the  morphol- 
ogy of  Filiaria  loa  as  well  as  on  all  cases  reported.  He  also  calls 
attention  to  the  cases  vv'hich  have  been  recorded  and  wrongly  as- 
signed to  Filaria  loa. 

In  the  same  year  Livon  and  Penaud*  (1906)  observed  a  fe- 
male, but  did  not  describe  it.  They  report  more  fully  in  regard 
to  the  micro-filarise  observed  in  the  blood,  urine  and  saliva  of 
the  host  as  well  as  those  which  were  hatched  from  eggs  which 
had  been  artificially  removed  from  the  adult  females.  Later 
Billet^  (1906)  described  a  male  24  mm.  x  0.4  mm.  He  states 
that  he  agrees  with  Manson,  Bernard,  Blanchard,  Ozzard.  Penel 
and  Wurtz.  tie  does  not  refer  to  Looss'  description,  and  he 
gives  but  few  measurements  and  no  drawings.  Where  he  cites 
Bernard  as  an  authority,  we  must  call  attention  to  the  fact  that 


■7. 

t 

1> 

U 
> 

.§1 
o  — 

Host 

From  wliat  aiia- 
toiuical  localitv 

Kl-.MAKKS 

Leuckaii 

1881 

Loanf,'-() 

Furoiiean 

Eye 

Mansnii 

1895 

W.  Africa 

" 

" 

1895 

0.25 

OK! 
Calahar 

" 

Tail    extremity   not    curved. 

l.udwi.i^ 

1895 

0.253X 
0.005 

Gahoon 
Kamerun 

1 1 

i< 

Specimens  injured  in  several  i)laces. 
Intestines    and    genital    organs    ]):\r- 

CjoIiI  C'oast 

tially  protruding. 

P.lancliard 

189( 
1899 

Frcncli 

" 

Eggs,  no  embryo. 

Cephalic  cone  less  and  not  so  clear 
as  in   male.      .\'o  head  pa])ill.-e. 

O/zard 

1 

1903 
1903 
1903 

1903 

Ni<itria 

Tail  not  sliarply  curved  as  in  female 
Spicules  do  not  protrude. 
Short  i)osterior  si)icule. 
Longer  anterior  spicule. 

Looss 

1904 
1904 

0.(1047 

Oold 
Coast 

? 

} 

S])icules   jiarlially    ])rotrude. 

Ward 

1906 
1906 
1906 

Bataufja 
Africa 

Tails  cnr\ed. 
Si)icules  ])rntrude. 

IIufFnian 
and 

191C 

Batan^^a 

American 

Eye 

Tail  curve<l. 

Si)icules  do  not  protrude. 

W^hcrry 

191C 
191C 

" 

'• 

" 

Tail  not  curved  as  much  as  male. 
Tail  nut  cur\ed  as  much  as  male. 

1910 

(l.()()6x 
0.279 

'• 

" 

" 

Only  anterior  20  mm.  preserved. 

] 

1 

~ 

1^ 

lis 
III 
1"" 

%z 

III 

!.  ' 

fnt'    %\ 

■| 

Ms 

|i 

■oi 

H 

H 

II 

Is 

1 

1 

KLsr.K. 

ill     i 

41* 
25-30 

35.5 
41 

0.3 
0.5 

0.5 

■ 

1,5 
3 

1.  j 

''ill'.  ,«■.'"■ 

ailaiial 

11.11(14 
(1,(1(17 

(1.(112 

deliralc 
at  tail 

11.11111 

ll.lKSv 
11.1125 

(I.255X 
(i.dUi 

l.nant;o 
W.  Africa 

OKI 
Calabar 

(laliooii 
Kanieruii 
i;<iM  Cast 

Kiinipean 

F.vc 

Tail    vxtr.niity   iml    itirvi-d 

Specimens  injured  in  several  i)laccs. 
Intcstim-s   and    genilal    organs   par- 
tially protruding. 

HliiiK-lianl 

1 
1899  1    i 

1 
1899  1    9 

1 

i 
1903  1    9 

1 
1903  1    9 

1 
I9:i3  1   i 

\ 

mi  I  i 

1 

22 

20 

55 
50 
30 

35 

0.435 
0.54 

0.55 

0.275 
0.175 

0.082 

? 

0.3 
0.175 

2.35 

4.4 

0.18 

last 
M  lip 

U.O 

5  pr^.  asy... 
4tli  pr. 
postanal 

Same  as 

11,11(1') 

Nn 

KreiK-li 

Nigeria 

1Ck(4>.  no  embryo. 

t'cphalic  cone  less  and  not  so  clear 
a>  in  male.     \.,  head  i.apilhe. 

Tail  not  sharply  curved  as  in  female 
Spicules  do  not  protrude. 
.Short  piislcrior  spicule. 
l.oiijiiT  anterior  spicule. 

l.„„s. 

1 

1904  \    i 

33 

0.4 

0.05 

0.084 

2.5 

1.2 

11.176 

5  prs. 

ll.llll'J 

(,.(,(,, 

M  tall 

li.ll!5v 

(1,(1(147 

(i..kl 
Cc.asl 

? 

? 

Sl.icules  partially   i.n.lrndc. 

1 
11(14  1    9 

52 

0.5 

0,07 

0.17 

0.17 

2.4 

lasl^ 

Kniie 

' 

\V;,rJ 

1906  1    <J 

mb  1  i 

16 
22 
25 

liataiipra 
Africa 

Tails  curved. 
Sl.icules  prntrud.-. 

lliilTiiian 

and 
Wherry 

1 

1 

1910  t    i 

- 
35 

n.35 

0.055 

0,168 

0.112 

3,5 

1.19 

U.IC.S 

5  prs. 

11.  (Ids  ate^- 

11.012  ex- 
cept ai  ex- 

11.(1(16 

(l.dlS 

delieale 
at  tail 

HalaliKa 

Aiiicricai 

Kye 

Tail  curved. 

Spicules  [In  not  (.rolrnde. 

1910  1    9 

50 

0.5 

0.084 

0.192 

2.1 

4,2 

last 

11.1115 

Tail  nnt  curved  as  much  as  male. 

1910  j    9 

55 

0.5 

0.182 

1 

Tail  n.it  curved  as  (uuch  as  male. 

1910  '    9 

1 

(l.dd6x 
(1,279 

( Inly  (...terior  20  ...m.  preserved. 

•  Mcasu 

e,nen 

s  civi-i 

liineter 

s  or  fr 

clinlis 

hereof 

( 

r 


HUFFMAN  N     AND     WHERRY  83 

the   male   Filaria   loa   reported   by    Bernard    was    identified   by 
Blanchard. 

Wurtz  and  Nattan-Larrier^°  (1907)  reported  a  new  observa- 
tion of  Filaria  loa,  but  they  did  not  describe  the  Filaria  which 
was  removed  from  the  eye  nor  did  they  excluse  other  diseases 
which  might  have  caused  the  various  symptoms  shown  by  their 
patient. 

Thus,  with  the  aid  of  Ward's  critical  bibliography  up  to 
January  1,  1906,  and  a  review  of  the  literature  since  then,  we 
have  gone  over  the  various  descriptions  of  Filaria  loa,  and  these 
show  the  necessity  of  recording  further  descriptions  of  the  adult 
form  of  this  species. 

The  specimens  examined  by  us  were  kindly  placed  at  our  dis- 
posal by  Dr.  Emil  Blunden,  of  Cincinnati,  who  had  removed 
them  himself  from  his  wife's  eyes.  The  infection  was  appar- 
ently contracted  in  1907  outside  of  Batanga,  Cameroon,  West 
Africa.  In  all  seven  loa  have  been  extracted  to  date.  Our  spec- 
imens comprise  two  females  extracted  in  Africa;  a  male  and 
one  female,  w^iich  had  been  broken  off  20  mm.  back  of  the  head, 
extracted  in  America.  The  first  three  specimens  were  in  perfect 
condition,  and  had  been  preserved  in  10  per  cent,  chloral  hy- 
drate. Before  examination  they  were  placed  in  70  per  cent,  alco- 
hol containing  5  per  cent,  glycerine  heated  to  60°  C.  These  un- 
injured specimens  were  of  a  brownish  yellow  color  and  be- 
came sufficiently  clear  for  the  purpose  of  studying  their  internal 
structure.  The  thread-like  body  of  each  remained  in  a  slightly 
irregular,  compound  curve.  Each  worm  without  any  stretching 
and  without  difficulty  was  temporarily  placed  upon  a  glass  slide 
and  covered  with  alcohol-glycerine  solution  sufficient  to  support 
a  cover  slip.  In  this  way  the  worm  could  be  turned  and  ob- 
served from  every  aspect.  We  paid  considerable  attention  to 
those  structures  which  had  been  variously  described  by  others. 
The  fourth  specimen  had  remained  in  tap-water  for  forty-eight 
hours.    It  did  not  become  clear,  and  remained  very  white. 

Before  describing  each  of  these  specimens  separately,  we  will 
mention  wherein  our  observations  dififer  from  those  of  previous 
authors ;  we  do  not  find  the  bosses  on  the  cuticle  to  be  so  high 
as  previous  observers  found  them.     Their  average  height  upon 


84  DANDRIDGE    MEMORIAL 

our  specimens  is  equal  to  one-half  the  thickness  of  the  cuticle. 
We  find  the  cuticle  thicker  than  that  of  the  specimens  either  of 
Looss  or  of  Blanchard.  Ludwig  reported  the  cuticle  as  thicker 
than  we  do,  but  he  was  working  on  a  female  specimen  which 
had  been  injured  and  partly  emptied  of  its  intestine  and  genital 
organs.  Like  Ludwig,  and  differing  from  Looss,  we  find  very- 
delicate  transverse  striae  in  the  tail  of  the  female.  In  one  fe- 
male the  posterior  oviduct  passes  to  the  very  tip  of  the  tail,  and 
these  striae  are  not  seen  so  clearly  as  in  the  other,  wherein  the 
posterior  oviduct  turns  upon  itself  to  pass  forward  without  en- 
tering the  curved  portion  of  the  tail.  Naturally  in  the  litter  more 
light  may  pass  through  the  tail,  making  careful  observation  of 
both  layers  of  the  cuticle  less  difficult,  and  thus  accounting  for 
the  above  difference  between  Ludwig  and  Looss,  because  in  the 
former's  specimen  the  posterior  oviduct  did  not  pass  back  into 
the  curved  portion  of  the  tail,  while  in  the  latter's  specimen  it 
did. 

Like  Ward's  and  Billet's,  bnt  differing  from  that  of  Looss,' our 
male  presents  a  distinctly  well-curved  tail.  In  regard  to  the  cir- 
cumnal  papillae  of  the  male  and  their  arrangement,  we,  like  Man- 
son,  do  not  find  such  marked  symmetry  that  we  should  lay  stress 
upon  it.  When  we  carefully  observed  the  papilla  from  the  ven- 
tral aspect  they  appeared  symmetrical,  but  one  might  easily  judge 
those  on  the  left  side  to  be  larger  and  less  close  together.  We 
do  not  find  anything  to  indicate  the  appearance  of  orifices  on  the 
summits  of  the  largest  pair  of  papilla  as  Billet  did.  Like  Oz- 
zard,  we  find  the  anus  of  the  female  at  a  greater  distance  from 
the  tip  of  the  tail  than  does  Looss. 

In  the  main  we  can  corroborate  Looss'  anaromical  descrip- 
tions. Probably  through  a  typographical  error  Looss  refers  to 
the  embryo  as  0.035  to  0.37  mm.  x  0.022  mm.  The  0.37  mm. 
should  be  0.037  mm.  We  were  fortunate  enough  to  observe 
some  free  embryos,  and,  like  Ludwig,  we  find  them  to  have 
distinct  sheaths.  This  seems  important,  as  Manson  at  one  time 
did  not  believe  the  embryo  had  a  sheath. 

The  drawings  and  sketches  of  Filaria  loa,  copied  in  most 
treatises  on  parasites,  are  generally  misleading.  The  spicules 
are  represented  as  of  similar  size  and  disproportionately  long. 


HUFFMANN    AND    WHERRY.  85 

The  cuticular  bosses  and  circumanal  papillae  are  represented  dis- 
proportionately large.  The  bosses  sometimes  called  tubercles  or 
buckles,  appear  to  us  to  be  elevations  or  a  portion  of  the  outer 
layer  of  the  cuticle,  and  their  contents  are  absolutely  clear,  and 
do  not  show  any  cellular  structure. 

At  this  point  we  should  call  attention  to  the  fact  that  the  vulva 
is  not  at  the  junction  of  the  anterior  one-fourth  with  the  posterior 
three-fourths  of  the  body,  as  erroneously  stated  in  The  Animal 
Parasites  of  Mmi  (Braun,-  1906).  Ludwig  is  responsible  for 
this  mistake,  as  he  could  not  find  the  genital  opening  of  the 
female,  and  decided  that  it  was  in  that  portion  of  his  specimen 
which  had  been  mutilated.     He  also  mislocated  the  anus. 

Scheube^  (1903)  states  that  the  Filaria  loa  female  rarely  at- 
tains the  length  of  70  mm.  Maurel's  case,  reported  by  Trucy  in  a 
paper  on  the  Guinea-worm,  is  responsible  for  this  statement. 
Scheube  is  also  in  error  when  he  refers  to  Guyot,  1838,  under 
the  literature.     It  should  be  Guyon.     (Ward,  1906.) 

DESCRIPTION  O?  OUR  SPECIMENS. 
THE  MALE. 

External  structure. — The  male  is  35  mm.  long.  The  tip  of 
the  anterior  extremity  is  0.056  mm.  in  diameter.  At  the  center 
of  the  tip  is  the  oral  opening.  At  the  base  of  the  cephalic  cone, 
which  is  0.07  from  the  tip,  it  is  0.14  mm.  in  diameter. 

From  the  base  of  the  cephalic  cone  the  body  gradually  in- 
creases in  diameter  until  it  reaches  its  greater  circumference 
with  a  diameter  of  0.35  mm.  at  a  distance  of  0.7  mm.  from  the 
anterior  end.  This  maximum  diameter  of  0.35  mm.  is  main- 
tained throughout  the  remainder  of  the  anterior  one-sixth  of  the 
entire  body  length,  whence  it  gradually  and  evenly  diminishes  in 
circumference  down  to  the  rounded  tip  of  the  posterior  extrem- 
ity. The  posterior  extremity  is  curved  ventrally  like  a  shep- 
herd's hook,  and  presents  ano-genital  opening  on  its  ventral 
aspect,  0.112  mm.  distant  from  tip.  At  the  ano-gtrntal  opening  it 
is  0.168  mm.  in  diameter. 

The  cuticle  is  0.012  mm.  thick.  At  the  extremities  it  gradually 
becomes  reduced  in  thickness,  reaching  a  minimum  of  0.008  mm. 
It  consists  of  an  outer  harder  layer  and  an  inner  softer  layer. 


86  DANDRIDGE     MEMORIAL 

With  the  exception  of  that  covering  the  anterior  extremity  for 
a  distance  of  3.5  mm.  from  the  oral  opening  and  the  posterior 
extremity  for  a  distance  of  1.19  mm,  from  the  tip  of  the  tail 
the  cuticle  presents,  at  irregular  distances,  bosses  which  arise 
from  the  outer  layer  of  the  cuticle.  These  bosses  are  not  hemi- 
spherical. Their  average  diameter  at  the  base  is  0.018  mm.,  and 
their  average  height  0.006  mm.  or  one-half  the  thickness  of  the 
cuticle. 

On  the  ventral  aspect  of  the  posterior  extremity  there  are  five 
pairs  of  papillae.  The  anterior  pair  is  the  largest.  They  success- 
sively  decrease  in  size  from  the  anterior  to  the  most  posterior 
pair,  which  is  almost  at  the  tip.  The  ano-genital  opening  is  par- 
tially between,  but  mostly  posterior  to  the  third  pair.  If  we 
could  not  discern  the  interior  structure  we  should  simply  note 
slight  undulations  of  the  cuticle  instead  of  papilla. 

The  cuticle  is  non-striated,  with  the  exception  of  that  cover- 
ing the  posterior  extremity.  Here  transverse  stria;  are  perfectly 
discernible,  and,  by  focusing,  they  may  be  seen  to  extend  across 
the  entire  width  of  the  body  of  this  portion.  Upon  close  ob- 
servation it  may  be  noted  that  the  outer  and  inner  epiderm  is  not 
striated. 

Internal  Structure. — ^Beginning  at  the  oral  oriiice  is  the 
esophagus,  formed  by  large  cylindrical  cells.  On  either  side  there 
is  a  dark  granular  mass,  due  to  nerve  cells  and  probably  to  some 
glandular  elements.  For  a  distance  of  0.2  mm.  the  lateral  bands 
and  the  powerful  musculature  may  be  observed  with  consid- 
erable clearness  when  the  beginning  of  the  intestine,  and  greater 
thickness  of  the  body  make  the  internal  parts  less  easily  dis- 
cerned. However,  the  intestine  and  the  testicle  can  be  deter- 
mined throughout  the  entire  body.  In  the  anterior  part  the  tes- 
ticle is  composed  of  spermatoblasts  of  polyhedral  shape.  Lower 
in  the  posterior  portion  free  spermatozoa  occur;  0.114  mm.  above 
the  ano-genital  opening,  when  viewed  from  the  left  side  we 
observe  the  upper  thicker  end  of  one  of  the  spicules.  It  appears 
to  be  transversely  concave  and  transversely  striated  near  its  up- 
per end.  Upon  close  study  we  are  not  sure  but  that  these  coarse 
striae  are  caused  by  the  spermatozoa  in  the  adjoining  ejaculatory 
duct,  where  they  occlude  the  light  from  passing  through  the  highly 


HUFFMAN  N     AND    WHERRY  87 

refractile  and  dense  edges  of  the  chitinous  spicule.  The  spicule 
gradually  diminishes  in  size  and  curves  towards  the  anal  open- 
ing, just  before  reaching  which  it  is  lost  to  view.  Neither  spicule 
projects  from  the  ano-genital  opening.  It  is  0.28  mm.  from  the 
tip  of  the  posterior  extremity  of  the  body  to  the  base  or  anterior 
end  of  the  longer  spicule. 

Upon  turning  the  worm  over  and  examining  it  from  the  right 
side,  a  shorter  spicule,  like  the  lower  end  of  the  long  one,  is  seen 
partially  crossing  the  longer  one  just  inside  the  ano-genital 
opening. 

Anterior  to  the  anus  there  are  three  of  the  five  pairs  of 
papillae.  They  are  distinct  pyriform  masses  projecting  from  the 
musculature,  and  cause  the  papillae  noted  when  examining  the 
cuticle.  These  papillae  do  not  protrude  from  the  skin  so  much 
as  their  interior  granular  portions  protrude  as  distinct  pyriform 
projections  from  the  musculature.  Bollett  suggests  that  the  larg- 
est pair  may  give  rise  to  a  secretion  of  some  aid  to  the  act  of 
copulation.  The  anterior  pair  are  situated  anteriorly  to  the  ano- 
genital  opening  at  a  distance  equal  to  the  length  of  the  post-anal 
portion  of  the  tail.  This  pair  is  the  largest  and  most  perfectly 
pyriform.  The  pairs  are  successively  smaller  and  situated  closer 
together.  Between  the  two  rows  of  papillae  there  is  a  slight 
concavity,  but  the  ano-genital  opening  is  at  a  slight  elevation. 

THE  FEMALES. 

External  Structure. — The  first  female  examined  is  50  mm. 
long  and  0.5  mm.  at  its  greatest  diameter.  It  is  0.084  mm. 
across  the  tip  of  the  cephalic  cone.  The  base  of  the  cone  is 
0.084  mni.  from  the  tip,  and  at  this  point  the  diameter  is  0.182 
mm. 

At  a  distance  of  about  0.7  mm.  from  the  anterior  end  the 
maximum  diameter  of  0.5  mm.  is  reached.  This  diameter  is 
maintained  throughout  the  anterior  one-fifth  of  the  entire  body 
length,  whence  it  gradually  and  evenly  diminishes  in  circumfer- 
ence back  to  the  rounded  tip  of  the  pvosterior  extremity,  which 
is  partially  curved  ventrally,  but  not  so  much  as  the  tail  of  the 
male. 

The  anus  is  0.21  mm.  from  the  tip  of  the  posterior  extrem- 


88  D  A  N  D  R  I  D  G  E     MEMORIAL 

ity  on  the  ventral  aspect.  At  the  anus  the  diameter  of  the  body 
is  0.192  mm. 

The  cuticle  is  of  the  same  thickness  as  in  the  male.  At  2.1 
mm.  from  the  anterior  tip  is  the  genital  opening,  which  causes  a 
slight  protuberance. 

The  first  boss  is  4.2  mm.  from  the  anterior  head.  From 
here  on  the  bosses  occur  at  irregular  intervals,  and  are  more 
numerous  than  in  the  male.  Furthermore,  they  are  found  upon 
the  posterior  extremity  back  to  the  very  tip. 

In  the  slightly  curved  posterior  portion  the  cuticle  is  striated, 
but  not  so  plainly  as  in  the  male.  This  appearance  may  be  due 
to  a  crimping  of  the  inner  softer  layer,  yet  it  shows  most  dis- 
tinctly beyond  the  anus,  where  there  is  no  bending  of  the  tail. 

Internal  Structure. — The  cephalic  cone  is  translucent,  as  the 
heavy  musculature  does  not  project  into  it.  At  its  base  and  along 
the  esophagus  there  are  dense  granular  masses,  which  may  be 
glandular  or  nervous  tissue.  These  obscure  the  light  to  such  a 
degree  that  we  cannot  discern  any  papillae  about  the  head. 

At  0.35  mm.  posteriorly  we  come  to  a  loop  of  the  anterior 
oviduct.  Within  the  oviduct  we  can  discern  numerous  ova  or 
embryos.  The  oviduct  is  0.07  mm.  in  diameter,  and  does  not 
cross  itself  anteriorly  to  the  vulva.  The  esophagus  and  intestine 
are  pushed  aside.  The  musculature  occupies  a  considerable  vol- 
ume at  this  point. 

The  vagina  curves  backward  a  short  distance  (0.2  mm.), 
then  suddenly  inwards,  and  is  lost  to  view  on  account  of  the 
opacity  of  the  worm.  Just  before  we  come  to  the  curve  in  the 
posterior  extremity  the  posterior  oviduct  bends  upon  itself,  and 
we  can  discern  numerous  large  ova.  The  intestine  follows  the 
greater  curvature  until  about  opposite  the  anus,  when  it  can  be 
seen  distinctly  crossing  from  the  dorsal  wall  to  the  anus. 

The  second  female  examined  is  55  mm.  long  and  0.5  mm. 
wide,  and  presents  these  differences:  0.49  mm.  from  the  an- 
terior tip  we  come  to  the  loop  of  the  anterior  oviduct  that  com- 
pletely crosses  itself  anteriorly  to  the  vulva,  which  is  1.75  mm. 
from  the  tip  of  the  head.  The  vagina  runs  parallel  to  the  wall, 
directly  from  the  vulva  backwards  a  distance  of  5.6  mm.,  where 
it  becomes  a  bifid  uterus!    It  presents  thick  walls.    Near  the  pes- 


HUFFMAN  N    AND    WHERRY  89 

terior  extremity  the  two  loops  of  the  posterior  oviduct  seem  to 
fill  the  entire  body  cavity,  and  the  ova  or  embryos  are  not  so 
closely  packed.  The  larger  ova  measure  0.015  mm.  x  0.024  mm., 
and  appear  as  coiled  embryos.  At  this  part  the  intestine  is  dis- 
cernible, as  well  as  two  loops  of  the  posterior  ovary,  which  over- 
lie the  posterior  oviduct  in  braid-like  fashion.  In  this  female  the 
posterior  oviduct  passes  back  into  the  very  extremity  of  the  tip, 
where  larger  ova  are  discernible.  The  anus  is  0.21  mm.  from 
the  tip  of  the  tail.    The  diameter  at  the  anus  is  0.182  mm. 

The  third  female  examined  had  been  broken  off  about  20  mm. 
from  the  head.  This  specimen  was  white,  and  did  not  become 
clear  when  treated  with  the  alcohol-glycerine.  It  had  been 
placed  in  ordinary  tap-w^ater,  and  was  not  preserved,  nor  were 
the  embiyos  examined  until  forty-eight  hours  later.  The  em- 
bryos were  motionless  and  probably  dead. 

In  so  far  as  it  could  be  examined  it  was  like  the  second  fe- 
male. It  was  from  this  worm  that  the  free  embryos  were  ob- 
tained. They  occurred  in  great  numbers.  Only  two  were  meas- 
ured. One  is  0.279  mm.  long,  including  the  sheath  projecting 
from  the  head  end.  The  sheath  projects  beyond  the  head  0.009 
mm.  The  greatest  diameter  is  0.006  mm.  The  other  is  0.294 
mm.  long  x  0.006  broad.  In  both  the  sheath  projects  beyond  the 
point  of  the  tapering  tail  0.015  mm.  The  anterior  end  is  bluntly 
rounded,  while  the  tail  is  finely  drawn  out.  The  cuticle  is  smooth 
and  the  interior  of  the  body  appears  to  be  finely  granular.  We 
were  unable  to  observe  the  V  spot. 

REFERENCES. 

1.  Billet,  M.  A.  (1905)  :  Un  nouveau  cas  de  Filaria  loa  male.  Compt. 
Rend.  Soc.  Biol.,  Paris,  vol.  Ixi,  No.  34,  pp.  507-508. 

2.  Braun,  M.  (1905)  :  The  Animal  Parasites  of  Man.  Tr.  from  German 
by  P.  Falcke.  Revised  and  brought  up  to  date  by  L.  W.  Sambon,  M'.D., 
and  K  V.  Theobald,  M.A. 

3.  Leuckart,  R.  (1886)  :  Parasites  of  Man  and  the  Diseases  which  Pro- 
ceed from  Them.  Tr.  from  the  German,  with  the  co-operation  of  the  au- 
thor, by  W.  E.  Hovle. 

4.  Li  von,  J.  (fils)  et  Penaud  (1906)  :  Un  cas  de  Filaria  loa  avec  oedemes 
intermittents,  microfilaires  dans  le  sanp,  I'urine  et  la  salive;  eosinophilic 
marquee,  fitude  de  la  filaire  adulte  et  des  ses  oeufs — leur  evolution.  Nais- 
sance  des  microfilaires  et  etude  morphologique  de  ces  parasites  embryon- 
aires.    Compt.  Rend.  Soc.  Biol.,  Paris,  vol.  Ixi,  No.  35,  pp.  510-511. 

5.  Looss,  A.  (1904)  :  Zur  Kentniss  des  Baues  der  Filaria  loa,  Guyot. 
Zool.  Jaltrb.,  Abt.  Syst.,  vol.  xx,  pp.  549-574;  mit  Tafeln. 


90  DANDRIDGE     MEMORIAL 


(1905)  :  "Filaria  loa  Guyot  1778."    Handbuch  der  Tropenkrank- 


heiten,  herausgegeben  von  Dr.  C.  Mense,  vol.  i,  pp.  177-179,  with  bibliog- 
raphy. 

6.  Manson,  P.  (1901)  :  "Filaria  loa"  in  "A  System  of  Medicine,"  edited 
by  T.  C.  Allbutt,  vol.  ii,  p.  1059. 

7.  Nattan-Larrier,  L.,  et  Parvu  (1909)  :  La  valeur  de  I'eosinophilie  chez 
malades  porteurs  de  Filaria  loa.  Arch  d.  malad.  cceur,  Paris,  vol.  ii,  pp. 
635-649,  3  pi. 

8.  Scheube,  B.  ("1903)  :  The  Diseases  of  Warm  Countries.  Tr.  from 
German  by  Pauline  Falcke. 

9.  Ward,  H.  B.  (1909)  :  Studies  on  Human  Parasites  in  North  America, 
1.  Filaria  loa.  Studies  from  the  Zoological  Laboratory,  No.  63 ;  Univer- 
sity Studies,  vol.  v,  p.  271.  Also  published  in  Journal  Inf.  Dis.,  vol.  iii,  jpp. 
37-90;  Bull.  Univ.  Nebraska  Coll.  of  Med.,  Lincoln,  Neb.,  vol.  i.  No.  1, 
January,  1906,  pp.  1-75,  with  complete  critical  bibliography. 

10.  Wurtz,  R.,  et  Nattan-Larrier,  L.  (1907)  :  Nouvelle  observation  de 
Filaria  loa.  Archives  de  Med.  ex  p.  et  d'Anat.  path.,  Paris,  vol.  xix,  pp. 
558-564. 


THE  EMBRYOS  OF  P^ILARIA  LOA.* 


BY  OTTO  V.    HUFFMAN,    M.D. 


The  embryo  of  Filaria  loa  has  never  been  fully  studied  or  de- 
scribed, and  for  this  reason  the  hypothesis  put  forward  by  Man- 
son  that  the  Filiaria  diiirna  is  the  larva  of  Filaria  loa  remains 
unproven.  When  Manson  suggested  this  connection  he  had  at 
hand  some  sketches  of  embryos  which  Leuckart  had  made  and 
sent  to  him.  As  these  sketches  were  not  of  sufficient  aid  to  es- 
tablish the  identity  of  the  embryos  with  the  larvae  found  by  him 
in  the  blood,  and  as  no  metamorphosis  takes  place  in  the  larvae 
while  circulating  in  the  blood,  it  is  reasonable  to  suppose  that 
they  must  have  been  rather  crude  sketches.  However,  the  hy- 
pothesis came  to  be  accepted  because  it  was  well  supported  by 
the  fact  that  the  two  v/orms  have  the  same  geographical  distri- 
bution and  also  by  the  occasional  discovery  of  both  in  the  same 
host.  At  the  same  time  that  this  hypothesis  was  advanced,  Man- 
son  changed  the  name  from  Filaria  sangiwiis  hominis  major  to 
Filaria  hominis  diurna,  and  said  that  the  species  was  practically 
indistinguishable  on  morphological  grounds  from  the  well-known 
Fl'aria  sanguinis  hominis  of  Lewis  (Filaria  nocturna,  ]\Ianson), 
i.e.,  Filaria  hancrofti.  This  fact  made  it  all  the  more  necessary 
to  observe  embryos  taken  from  an  adult  female  Filaria  loa  be- 
fore venturing  to  state  the  origin  of  the  larva;  found  in  the 
blood. 

Only  one  author  has  stated  that  Filaria  loa  is  the  adult  form 
of  the  Filaria  diurna  of  Manson,  and  he  had  nothing  new  in 
the  way  of  evidence  to  justify  him  in  making  such  a  statement. 
This  was  Brumpt  who  had  observed  in  the  blood  of  a  patient  a 
microfilaria  which  he  had  described  as  a  new^  species — Filaria 
boiirgii.  Upon  the  death  of  this  patient  he  found  in  the  heart 
a  portion  of  a  female  worm  without  head  or  tail,  but  presenting 
cuticular  bosses  like  those  of  Filaria  loa.     After  returning  to 


*  From  Parasitology,  vol.  iv,  No.  1,  March,  1911. 

91 


92  DANDRIDGE     MEMORIAL 

Paris  he  compared  his  specimens  of  microfilariae  with  those  de- 
scribed by  Manson  as  Filaria  diurna,  and  he  decided  that  they 
were  identical,  and  the  mere  association  of  these  microfilariae 
with  adult  Filaria  loa  in  the  same  host  led  him  to  make  the  above 
statement. 

In  1906  Livon  and  Penaud  observed  some  embryos  of  Filaria 
loa  which  had  been  artificially  removed  from  an  adult  female, 
but  their  description  is  quite  brief  and  unaccompanied  by  any 
figures. 

Recently  Burrows  has  published  an  article  on  the  relation 
of  F.  diurna  to  F.  loa,  but  both  of  the  adult  F.  loa  removed  from 
hi;  patient  were  mutilated,  and  therefore  the  opportunity  of  ob- 
taining embryos  from  the  female  was  lost. 

I  have  been  more  fortunate  than  my  predecessors  in  being 
able  to  observe  and  study  a  live  female  F.  loa,  fully  matured, 
with  uteri  filled  with  ripe  embryos.  These  €mbr}os  have  the 
same  dimensions  as  those  recorded  for  F.  diurna,  and  are  idetv- 
tical  with  them  in  other  respects. 

Since  Huffman  and  Wherry  have  already  described  the  anat- 
omy of  the  adult  F.  loa,  I  take  this  opportunity  of  adding  a  few 
notes  in  regard  to  the  living  adult  from  which  the  embryos 
were  obtained. 

Dr.  Emil  Blunden  brought  to  the  laboratory  a  live  female 
Filaria  loa  62.5  mm.  in  length  which  he  had  just  removed  from 
the  eye  of  Mrs.  B.  This  is  the  eighth  specimen  removed  from 
Mrs.  B.  The  worm  had  been  placed  in  warm  tap  water,  and 
there  was  no  doubt  about  its  being  alive,  because  it  continually 
performed  all  manner  of  movements.  The  worm  was  very 
\v'hite,  the  cephalic  extremity  and  the  tail,  into  which  the  genital 
organs  did  not  enter,  were  translucent.  The  mtestine,  being 
black,   was  quite  visible  throughout  its  course. 

The  worm  was  placed  on  a  large  glass  slide  so  as  to  be  ob- 
served under  the  microscope.  The  cephalic  papillae  were  easily 
discerned,  but  did  not  project  from  the  cuticle  as  much  as  their 
granular  contents  projected  from  the  musculature.  The  esoph- 
agus was  long  and  narrow,  and  not  bordered  by  such  big  cylindri- 
cal cells  as  in  preserved  specimens ;  moreover  it  was  clear,  and 
appeared  to  have  narrow  culs-de-sac  opening  into  it  from  either 


HUFFMANN.  93 

side.  The  viscera  occupied  less  than  two-thirds  of  the  diameter 
of  the  body,  and  the  musculature  was  clear  and  translucent. 
The  distance  from  the  tip  of  the  head  to  the  most  anterior  loop 
of  the  oviducts  was  about  twice  as  great  as  in  preserved  speci- 
mens. As  the  worm  became  partially  dry  the  cuticular  bosses 
on  top  became  visible  as  warty  plaques,  like  these  represented 
in  Blanchard's  well  known  drawing.  This  circumstance  ac- 
counted for  his  description  which  we  w^ere  previously  unable 
1o  reconcile  with  the  neat  transparent  bosses  observed  by  us 
in  preserved  specimens.  The  tail  was  carried  well  curved,  with 
a  slight  spiral  twist. 

In  order  to  keep  the  worm  active,  the  warm  water  in  which 
it  was  kept  was  frequently  changed.  After  examining  the  struc- 
ture of  the  parasite  we  decided  to  try  some  experiments  to  see 
if  we  might  cause  the  birth  of  some  embryos.  With  the  pos- 
terior two-thirds  of  the  worm  in  warm  water  and  the  anterior 
third  projecting  on  to  the  dry  portion  of  the  slide,  we  covered 
the  anterior  extremity,  as  far  back  as  the  vulva,  with  a  large 
drop  of  fresh  human  blood.  The  worm  immediately  gave  evi- 
dence of  distaste  for  the  blood  by  withdrawing  its  head  and 
moving  away.  An  attempt  to  produce  abortion  by  pressure  and 
by  irritation  was  then  made,  but  without  avail.  Then  the  worm 
was  placed  over  night  in  a  small  phial  of  w-arm  water  in  an 
incubator  at  33°  C.  The  next  morning  the  worm  was  quite  in- 
active, and  upon  examining  the  water  no  ova  or  embryos  were 
found.  Many  bacteria  were  present,  as  the  water  had  not 
been  sterilized,  nor  had  the  worm  been  handled  in  an  aseptic 
manner  on  the  previous  day.  I  decided  to  section  the  body  near 
the  vulva  to  obtain  embryos  before  death  supervened.  One 
could  see  the  uteri  which  were  intertwined  with  the  loops  of  the 
oviducts,  they  were  distended  with  fully  developed  uncoiled  em- 
bryos packed  in  bundles  end  to  end. 

As  the  body  was  divided  transversely  with  a  sharp  scalpel, 
myriads  of  uncoiled  embryos  in  their  sheaths,  as  well  as  coiled 
embryos  in  their  sheaths  and  ova  escaped  into  the  drop  of  water 
on  the  slide.  The  embryos  were  alive,  as  shown  by  their  swing- 
ing their  anterior  one-half  from  side  to  side  or  by  lifting  the 
anterior  half  upwards.     They  were  not  locomotive.     No  spines 


94  D  A  N  D  R  I  D  G  E     MEMORIAL 

or  lips  were  seen.  No  forward  or  backward  motion  within  the 
sheath  occurred,  except  as  it  might  be  caused  by  outside  pres- 
sure. I  observed  coiled  embryos  start  the  process  of  uncoiling. 
This  seems  important,  as  Manson  has  held  that  the  sheath  of 
the  coiled  embryo  is  the  same  as  the  larval  sheath  observed  in  the 
blood,  while  Ludwig  and  Looss  believe  that  this  sheath  is  dis- 
carded before  birth.  Livon  and  Penaud  observed  the  disappear- 
ance of  the  egg  envelope  and  the  birth  of  the  embryo  with  its 
sheath.  We  observed  some  of  these  coiled  embryos  uncoil  and 
stretch  the  sheath  which  contained  them. 

Of  these  thousands  of  embryos  in  water  on  the  glass  slide  we 
made  a  number  of  fixed  preparations  to  be  variously  stained. 
Others  were  placed  in  wet  human  blood  preparations  sealed  with 
vaseline. 

Some  were  injected  into  the  subcutaneous  tissues  of  a  guinea- 
pig.  The  water  containing  some  of  them  v»'as  given  to  another 
guinea-pig  to  drink.  The  guinea-pigs  died  recently,  but  no  cause 
of  death  could  be  discovered. 

I  did  not  succeed  in  getting  the  embryos  to  butt  their  way 
out  of  their  sheaths  after  heating  a  blood  preparation  which  had 
been  chilled  on  ice,  as  described  by  ?>Ianson.  Nor  was  I  success- 
ful in  reviving  embryos  which  had  been  dried,  as  suggested  by 
the  same  author.  In  heating  a  wet  blood  preparation,  slight  cur- 
rents may  be  set  up.  which  cause  the  appearance  of  slight  motion 
on  the  part  of  the  embryo  and  give  the  appearance  of  butting. 
Measurements : 

Coiled  embryos  0.051  x  0.036  mm. 

Embryos  0.006  x  0.3      mm. 

Average  projection  of  sheath  anteriorly  0.009  mm. 

Average  projection  of  sheath  posteriorly  0.009  mm. 

Anterior  V  spot  0.09  mm.  from  head  end. 

Posterior  spot  0.06  mm.  from  tail  end. 

Livon  and  Penaud  give  the  length  as  0.3  to  0.35  mm.  and  the 
width  as  0.005  to  0.007  mm.  The  maximum  diameter  of  the 
embr3'Os,  0.006  mm.,  is  maintained  with  very  slight  diminution 
until  a  point  0.24  mm.,  from  the  head  end  is  reached,  where  the 
body  commences  to  taper  to  the  posterior  extremity.  The  pos- 
terior extremity  is  rounded.     It  is  not  sharply  pointed,  and  we 


HUFFMANN.  95 

cannot  conceive  such  a  tail  being  folded  upon  itself  within  the 
sheath,  as  described  in  the  table  given  by  Neveu-Lemaire.  At 
the  anterior  extremity,  v/hich  is  broadly  rounded,  there  are  two 
highly  refractile  black  specks ;  0.09  mm.  from  the  head  end  is  the 
ovoid  mass,  which  presents  the  anterior  V  spot.  This  ovoid 
mass  causes  a  slight  bulging  of  the  body  on  three  sides,  but  not 
on  the  fourth,  as  it  dees  not  extend  deeper  than  the  plane  of  the 
central  longitudinal  axis  of  the  body.  Within  this  clear,  highly 
refractile  mass  there  are  two  black,  granular  specks,  separated 
sufficiently  to  give  rise  to  the  V  (spot),  which  ii  an  optical  ef- 
fect. The  point  of  the  V  is  directed  to  the  periphery.  0.06  mm. 
from  the  tail  end  is  a  similar,  but  smaller,  ovoid  body  and  V 
spot.  When  the  ovoid  masses  are  seen  from  a  direction  mid- 
way between  that  which  shows  their  broadest  cimensions  and 
that  which  shows  their  least  dimensions,  a  conic-il  papilla  is  ob- 
served which  has  its  apex  directed  laterally.  All  of  the  embryos 
have  these  spots,  and  they  are  not  properly  situated  in  relation 
to  the  length  of  the  embryo  to  represent  the  vulvar  and  anal 
openings,  as  suggested  by  Manson  and  by  Ashburn  and  Craig. 

In  the  stained  specimens  the  ovoid  masses  at  the  V  spots 
did  not  cause  a  bulging  as  in  the  live  specimens,  but  at  their  site 
there  was  a  slight  narrowing  of  the  body.  Throughout  the  body 
in  most  specimens  we  could  determine  the  stained  intestine.  Be- 
hind the  posterior  V  spot  the  intestine  was  not  stained  perfectly, 
but  in  sections  gave  rise  to  the  appearance  of  rod-like  bodies 
placed  end  to  end,  as  described  by  Ashburn  and  Craig.  These 
latter  authors  permitted  an  ellipsis  in  their  article  where  they 
state,  "At  about  the  middle  of  the  posterior  of  the  worm  are  sit- 
uated the  posterior  V  spot  and  the  papilla."  They  attempted 
to  describe  a  new  species  of  Filaria,  but  did  not  point  out  any 
determining  morphological  characteristics.  The  microfilaria 
which  they  described  as  a  new  species,  F.  philippinensis,  had  been 
previously  diagnosed  in  their  case  as  F.  diurna. 

The  interior  of  the  live  embryos,  with  the  exception  of  the 
refractile  specks  at  the  head  and  the  two  ovoid  masses,  is  en- 
tirely homogenous.  In  the  specimens  which  had  been  stained 
after  death  the  interior  was  made  up  of  irregular-rhaped  masses 
which  stained  deeply;  the  ovoid  masses  were  not  so  large.     The 


96  DANDRIDGE     MEMORIAL 

posterior  ovoid  mass  becomes  stained  before  the  anterior  mass, 
which  is  more  resistant  to  staining  solutions.  Embryos  stained 
by  a  very  dilute  solution  of  basic  fuchsin,  while  alive,  take  up 
the  stain  at  the  periphery  of  the  ovoid  masses  and  in  the  specks 
near  the  head  end.  They  also,  if  stained  by  a  stronger  solution, 
take  up  the  stain  in  the  rudimentary  intestine.  The  unstained 
live  embryos  are  white  and  translucent.  Those  which  were  placed 
in  human  blood  (wet  preparations)  appeared  of  the  same  color 
as  the  blood  plasma.  None  of  the  embryos  either  in  water  or 
blood  lived  more  than  an  hour  after  separation  from  their 
mother.  As  the  measurements  of  Filaria  diiirna  do  not  exceed 
those  of  the  embryo  of  Filaria  loa,  as  measured  by  Livon  and 
Penaud  and  by  myself,  it  is  fair  to  assume  that  no  great  changes 
take  place  while  in  the  blood,  and  that  a  study  of  viviparous  em- 
bryos should  give  results  not  unlike  those  of  a  study  of  the  filaria 
found  in  the  blood. 

Foran,  who  found  Filaria  diurna  in  the  blood  of  12.5  per 
cent,  of  826  natives  of  South  Nigeria,  noted  an  outflowing  of 
substance  at  the  anterior  V  spot.  This  may  have  been  due  to 
weakness  at  this  point,  for  Ashburn  and  Craig  roted  the  same 
in  some  of  their  specimens.  In  my  specimens  there  is  a  distinct 
bulging  of  the  ovoid  body  at  the  anterior  V  spot,  yet  it  cannot 
be  represented  to  be  so  large  as  in  the  sketch  of  Foran. 

Livon  and  Penaud  noted  that  some  had  blunt  tails.  Many 
years  ago  O'Nielly  and  O'Neil  observed  microfilarise  which  had 
two  specks  at  the  head,  alimentary  canals,  "bluntly  pointed"  tails, 
and  which  died  shortly  after  being  placed  upon  the  glass  slides. 

Some  of  the  embryos  which  I  had  left  sealed  in  water  were 
examined  two  weeks  later.  Degeneration  had  set  in;  besides 
the  two  V  spots,  which  did  not  show  up  so  clearly,  there  were 
other  spots  which  caused  some  confusion,  as  they  were  not  so 
distinct,  nor  were  they  in  focus  and  highly  refractile  at  the  same 
time  as  the  known  V  spots.  The  lines  and  anatomy  were  not 
so  clearly  defined  as  in  the  fresh  living  embryos,  and  it  is  easy 
to  see  why  the  filarias  found  in  the  blood  have  been  variously 
described.  When  all  of  the  various  preparations  were  examined 
one  month  later,  it  was  found  that  the  sheaths  of  the  specimens 
stained  by    fuchsin  were  no  longer  discernible ;  that  the  embryos 


HUFFMANN.  97 

in  the  wet  preparations  presented  irregular  masses  in  the  ante- 
rior portion  of  the  body  as  well  as  several  vacuoles  which  might 
be  taken  to  be  V  spots;  that  the  ovoid  masses  were  no  longer 
easily  distinguishable;  and  that  the  tails  had  lost  their  "plump- 
ness," being  flabby  and  drawn  out  posteriorly,  and  in  some  prep- 
arations which  had  been  disturbed  they  were  foMed  upon  them- 
selves. The  sheaths  of  some  of  the  embryos  in  the  wet  prepa- 
rations were  collapsed  and  extended  as  a  linear  projection  fore 
and  aft.  Hence  it  may  be  seen  that  it  is  impossible  to  determine 
any  definite  morphological  characteristics  except  in  fresh  em- 
bryos, which  present  a  definite  form,  granular  specks  at  the  head, 
alimentary  canal  and  two  ovoid  masses  definitely  situated  and 
representing  without  doubt  the  beginning  of  r.ndififerentiated 
organs. 

REFERENCES. 

Ashburn,  P.  M.,  and  Craig,  C.  F.  (1906)  :  A  New  Blood  Filaria  of 
Man — Filaria  philippinensis.  Am.  Jour.  Med.  Soc,  vol.  cxxxii,  pp.  435- 
443  (with  figures). 

Brumpt,  M.  C.  (1904)  :  Filaria  Joa  Guyot  est  la  forme  adulte  de  la 
microfilaire  designee  sous  le  nom  de  Filaria  diurna  Manson.  Conipt.  Rend. 
Soc.  Biol.,  Paris,  vol.  Ivi,  pp.  630-632. 

Burrows,  D.  (15,  i,  1910)  :  A  case  of  filarial  infection  in  which  both 
the  Filaria  loa  (male)  and  numerous  Filaria  diurna  were  obtained  to- 
gether.   Jour.  Trap.  Med.  and  Hyg.,  London,  vol.  xiii,  p.  25. 

(15,  ii,  1910)  :  The  relationship  of  Microfilaria  diurna  to  Filaria 

loa.    Jour.  Trop.  Med.  and  Hyg.,  London,  vol.  xiii,  p.  49. 

Foran,  B.  F.  C15,  ii,  1910)  :  Some  notes  on  filariasis  in  the  Ikotepene 
District,  South  Nigeria.  Jour.  Trop.  Med.  and  Flyg.,  London,  vol.  xiii.  p.  50. 

Huffman,  O.  V.,  and  Wherry,  Wm.  B.  (1911):  A  description  of  four 
Filaria  loa  removed  from  the  same  patient.  Parasitology,  vol.  iv,  p.  7.  PI.  2. 

Livon,  J.  (fils),  et  Penaud  (1906)  :  Un  cas  de  Filaria  loa,  avec  oedernes 
intermittents,  microfilaires  dans  le  sang,  I'urine  et  la  salive;  eosinophilie 
marquee,  fitude  de  la  filaire  adulte  et  de  ses  oeufs — leur  evolution.  Nais- 
sance  des  microfilaires  et  etude  morphologique  de  ces  parasites  embryon- 
aires.    Conipt.  Rend.  Soc.  de  Biol,  Paris,  vol.  Ixi,  No.  35,  pp.  510-512. 

Looss,  A.  (1904)  :  Zur  Kentniss  des  Baues  der  Filaria  loa.  Zool.  Jahrb. 
Syst.    Vol.  XX,  pp.  549-574. 

(1905)  :  "Filaria  loa  Guyot,  1778,"  in  Handb.  d.   Tropenkrank- 

heitcn,  herausgegcben  von  Dr.  C.  Mense  (Leipzig,  J.  A.  Barth),  vol.  i,  pp. 
177-179,  with  bibliography. 

Manson,  P.  (3,  i,  1891)  :  The  Filaria  sanguinis  hominis  major  and 
minor,  two  new  species  of  Hematozoa.    Lancet,  London,  vol.  i,  pp.  4-8. 

(1893)  :  The  geographical  distribution,  pathological  relations  and 

life  history  of  Filaria  sanguinis  hominis  diurna  and  of  Filaria  sanguinis 
hominis  Persians,  in  connection  with  preventive  medicine.  London :  Eyre 
&  Spottiswoode. 

(1897)  :  On  certain  new  species  of  Nematode  Hematozoa  occur- 
ring in  America.    Brit.  Med.  Jour.,  pp.  1S37-1838. 


98  D  A  N  D  R  I  D  G  E     MEMORIAL 

(1899)  :  On  filarial  periodicity.    Brif.  Med.  Jour.,  pp.  644-655. 

(1901):  "Filarida,"  in  A  System  of  Medicine,  edited  by  T.  C. 

Allbutt.     London:  McMillan  &  Co. 

(iii,    1910)  :    On    the   nature   and   origin   of   Calabar   swellings. 

Trans.  Soc.  Trap.  Med.  and  Hyg.,  vol.  iii,  pp.  244-256. 

Neveu-Lemaire,  M.  (1908)  :  Precis  de  Parasitologie  Humaine,  Paris 
(F.  R.  de  Rudeval),  pp.  482-487. 

Wherry,  Wm.  B.,  and  McDill,  John  R.  (1905)  :  Notes  on  a  case  of 
hematochyluria,  together  with  some  observations  on  the  morphology  of 
the  embrj'o  nematode,  Filaria  nocturna.   Jour.  Inf.  Dis.,  vol.  ii,  pp.  412-420. 


THE  SUCCESSFUL  TREATMENT  OF  A  CASE  OF 
ILLUMINATING  GAS  POISON.* 


BY  WILLIAM  RAVINE,  M.D. 


In  looking  through  the  Hterature  and  statistics  on  illuminating 
gas  poisoning,  one  is  struck  by  the  meagerness  of  the  reports 
and  by  the  variety  of  nomenclature  used  in  describing  cases. 
One  finds,  for  instance,  descriptions  under  the  titles  "Asphyxia," 
"Coal  Gas  Poisoning,"  "Carbon  Monoxid  Poisoning,"  "Poison- 
ing by  Noxious  or  Irrespirable  Gases."  In  the  several  instances 
the  cases  have  been  the  result  of  blowing  out  of  gas  lights,  either 
because  of  ignorance  or  with  suicidal  intent;  carelessness  in 
heaping  clothes  on  gas  fixtures  in  such  a  way  as  to  turn  the 
cocks ;  leaking  of  gas  fixtures ;  badly  constructed  or  worn-out 
stoves  and  fixtures ;  or,  as  in  my  case,  the  overturning  of  a  gas 
heater  by  an  individual  alcoholically  stimulated  to  the  point  of 
carelessness. 

During  the  years  1900-1910,  there  were  ten  cases  of  illuminat- 
ing gas  poisoning  at  the  City  Hospital  with  six  deaths. 

Illuminating   gas    contains : 

PER  CENT. 

Carbon  monoxid  12  to  28 

Carbon  dioxid   0.3 

Hydrogen    30.35 

Marsh  gas  21.45 

Nitrogen    6 

The  carbon  monoxid  in  this  mixture  of  gases  is  the  cause  of 
the  symptom-complex.  Carbon  monoxid  has  200  times  greater 
affinity  for  hemoglobin  than  oxygen,  and,  therefore,  the  life  of  an 
individual  can  continue  only  so  long  as  the  hemoglobin  is  able 
to  attach  enough  oxygen  to  itself  to  maintain  the  process  of  oxi- 
dation essential  to  life. 

*  From  The  Journal  of  the  American  Medical  Associaiion,  June  3,  1911, 
vol.  Ivi,  pp.  1651-1653. 

99 


100  dandridgp:   memorial 


SYMPTOMS. 

Carbon  motioxid  gas  has  no  influence  whatever  when  applied 
directly  to  nerve  and  muscle;^  when  it  acts  through  the  blood, 
however,  phenomena  appear  which  are  indicative  of  primary 
stimulation,  but  which  cause,  secondarily,  paralysis  of  the  ner- 
vous system.  Thus  there  occur  at  first  severe  headache,  great 
restlessness,  excitement  and  increased  cardiac  and  respiratory 
activity,  salivation,  tremor,  twitching  and  spasm,  followed  by 
mental  confusion,  exhaustion,  drowsiness  and  paralysis  and  loss 
of  consciousness,  labored  stertorous  breathing  and  finally  com- 
plete loss  of  sensibility,  and  death.  , 

Thompson,-  in  a  series  of  ninety  cases,  reports  a  leukocy- 
tosis in  eighty  cases,  which  he  thinks  is  due  to  some  specific 
action  of  the  gas,  and  which  is  similar  in  its  cause  to  the  leuko- 
cytosis that  occurs  in  ptomaine  poisoning. 

In  all  the  cases  reported  in  the  literature  there  was  in  the 
early  stages  a  subnormal  temperature.  The  maximum  temper- 
ature is  usually  attained  on  the  first  day.  The  highest  temper- 
ature reported  is  by  Steele.^  The  patient  was  a  girl  of  eight 
years,  who,  when  first  seen,  was  in  a  state  of  coma.  The  tem- 
perature began  to  rise  rapidly,  and  within  eight  hours  had  reached 
110°  F.,  accompanied  by  a  pulse  rated  at  215  per  minute.  In 
this  case  there  was  a  complete  recovery  in  six  days  following 
the  use  of  cold  sponges  and  inhalations  of  oxygen.  In  all  the 
cases  reported  the  pulse  has  been  accelerated  and  the  rhythm 
of  the  pulse  has  been  regular  during  the  coma. 

Physical  examination  of  the  lungs,  as  a  rule,  shows  no  abnor- 
malities except  in  fatal  cases,  and  in  these  the  findings  indicate 
a  terminal  edema.  The  urine  shows  no  special  characteristics. 
In  a  few  cases  there  was  a  transient  albuminuria.  The  pupils 
varied,  being  at  times  dilated,  at  times  contracted.  The  symptoms 
on  the  part  of  the  nervous  system  have  been  tremors,  muscular 
twitchings,  convulsions,  rigidity,  opisthotonos,  anesthesia  and 
headache.  Evidence  of  vasomotor  paralysis  is  found  in  burning 
sensations  in  the  skin,  especially  over  the  face  and  in  the  red- 
ness of  the  cutaneous  surfaces.  The  lips  and  extremities  appear 
bluish  and  cyanotic,  owing  to  the  peculiar  cherry-red  color  that 


RAVINE  101 

is  a  characteristic  of  carbon  monoxid,  but  which  does  not  obscure 
it.  Coma,  which  is  profound,  is  always  accompanied  by  stertor- 
ous breathing. 

Brunneaux*  has  reported  a  case  of  hemiplegia  following  gas 
poisoning ;  Finkelstein,  ^  one  of  dementia ;  Scotr,*  acute  mania 
with  recovery  after  ten  days;  Bruns/  disseminated  encephalo- 
myelitis. Alexander  Pauski*  reported  the  case  of  a  patient  ill 
for  months  with  paralysis  of  legs  and  arms,  sensory  and  speech 
disturbances,  amnesia  and  mental  weakness.  Becker^  reported  a 
case  of  multiple  sclerosis.  Bontecon^"  described  the  post-mortem 
findings  in  three  cases.  His  histories  related  that  the  faces  were 
pale,  that  the  expression  was  placid,  the  eyes  closed,  the  pupils 
neither  contracted  nor  dilated  and  the  conjunctivae  clear.  The 
muscles  on  section  were,  as  a  rule,  red.  The  lungs  were  cherry- 
red  in  color,  and  on  section  showed  a  moderate  edema.  There 
was  unnatural  amount  of  blood  found  in  the  pleura  or  pericar- 
dium. The  heart  was  empty  and  the  blood-vessels  contained  fluid 
blood.  The  left  ventricle  of  the  heart  was  contracted,  the  right 
ventricle  and  auricle  as  a  rule  were  dilated.  The  viscera  were 
all  of  a  pinkish  color.  In  the  case  of  Broadbent/^  there  was  a 
report  of  softening  of  the  lenticular  nucleus  and  the  posterior 
part  of  the  internal  capsule. 

DIAGNOSIS, 

The  diagnosis  of  illuminating  gas  poisoning  is  based  on  the 
history  of  the  case  and  on  the  presence  of  coma  with  stertorous 
breathing,  cherry- red  color  of  the  face  and  hands,  and  the  spec- 
troscopic analysis  of  the  blood,  which  demonstrates  the  presence 
of  carbon  monoxid  hemoglobin.  Carbon  monoxid  hemoglobin 
is  cherry-red  in  color  and  causes  the  appearance  in  the  spectrum 
of  two  absorption  bands  between  D  and  F,  not  unlike  the  oxy- 
hemoglobin bands.  The  further  means  of  recognition  is  the  so- 
dium test.  A  10  per  cent,  solution  of  sodium  hydroxid,  when 
added  to  carbon  monoxid  hemoglobin  and  heated,  gives  rise  to  a 
cinnabar  red  color.  This  same  test  applied  to  oxyhemoglobin 
produces  a  brownish-black  mass. 

TREATMENT. 

The  earliest  reported  treatment  for  illuminating  gas  poisoning 
is  that  of  .Struthers,"  who  advised  jugular  venesection,  on  the 


102  DANDRIDGE    MEMORIAL 

basia  of  his  experimental  work  on  animals.  Corssland  recom- 
mends the  hypodermic  use  of  15  mm.  of  a  10  per  cent,  solution 
of  nitroglycerin  injected  into  the  epigastrium.  Other  writers 
have  advised  electric  stimulation,  oxygen  inhalations,  cardiac 
tonics  and  venesection,  with  transfusion  of  defibrinated  blood 
or  normal  saline  solution.  One  author  in  his  treatment  of  a  case 
did  a  venesection  and  gave  an  enema  of  twenty  ounces  of  salt 
solution.  Heinicke,^^  in  a  report  of  twenty-five  cases  of  coal- 
gas  poisoning,  was  the  first  to  describe  intravenous  injection  of 
salt  solution. 

CASE   REPORT. 

January  19,  1911,  at  12:45  p.m.,  an  unknown  white  man 
(Case  No.  161,349)  was  admitted  on  the  East  Medical  Service 
at  the  City  Hospital  with  the  following  history : 

History. — The  inmates  of  a  house  at  223  George  Street  were 
alarmed  by  an  odor  of  gas,  and  on  investigation  they  found  that 
it  emanated  from  a  room  on  the  third  floor,  which  had  been  en- 
gaged the  night  before  by  two  men.  On  breaking  open  the  door 
they  found  the  two  men  lying  on  the  floor,  a  small  gas  heating- 
stove  overturned,  and  the  gas  escaping  from  the  attachment  on 
the  wall.  The  men  were  hastily  brought  to  the  hospital  by  the 
police  ambulance.  One  man  was  dead,  the  other  was  in  a  state 
of  coma.     The  latter  was  a  white  man  aged  about  forty. 

Exa'Hiination. — The  patient's  face  was  symmetrical,  somewhat 
reddened,  and  the  skin  about  the  lower  lids  blue.  The  lips  were 
blue  and  covered  with  a  white,  frothy  mucus.  The  pupils  were 
dilated  and  did  not  respond  to  light.  The  breath  was  fetid. 
There  was  no  odor  of  alcohol.  There  was  stertorous  breathing; 
no  marks  of  violence  either  about  head  or  the  body.  The  skin 
over  the  entire  body  was  dry  and  cold,  and  the  finger  tips  were 
blue.  The  pulse  was  strong  and  rapid — 130  beats  to  the  minute. 
The  rectal  temperature  was  97°  F.  There  were  no  convulsions. 
Examination  of  heart  and  lungs  revealed  nothing  of  note.  Ex- 
tremities were  relaxed.  There  was  no  Babinski  sign  or  ankle- 
clonus.  The  patient  did  not  respond  to  any  form  of  external 
stimulation.  Six  hundred  c.c.  of  a  dark  amber-colored  urine 
were  removed  by  catherization.  The  specific  gravity  was  1.025 
and  the  reaction  was  acid.  No  albumin,  sugar  or  casts  were 
present. 

Treatment. — The  patient  was  well  covered  with  blankets  and 
surrounded  by  hot-water  bottles,  and  was  given  1-30  gr.  strych- 
nine hypodermically.     The  median  basilic  vein  of  the  right  arm 


RAVI  N  E  103 

was  opened,  and  300  c.c.  of  blood  allowed  to  flow,  after  which  an 
intravenous  transfusion  of  1,200  c.c.  of  a  0.7  normal  saline  solu- 
tion was  given.  Inhalations  of  oxygen  were  also  given.  Three 
hours  later  the  face  was  somewhat  reddened  and  the  patient  was 
perspiring,  but  was  still  comatose.  Temperature  was  100°,  pulse 
136,  respiration  32.  Caffein  sodium  benzoate,  gr.  2,  given  hypo- 
dermically  every  four  hours.  After  another  three  hours  the  pa- 
tient responded  somewhat  to  external  stimulation,  but  was  still 
comatose.  Temperature  was  101°,  pulse  120,  respiration  36. 
At  the  end  of  another  three  hours  the  condition  was  about  the 
same;  temperature  101°,  pulse  128,  respiration  32.  On  the  sec- 
ond day  after  entering,  the  house  the  face  and  hands  of  the  pa- 
tient had  assumed  a  distinct  cherry  hue.  The  man  was  drowsy, 
responded  very  slowly  to  questions,  after  answering  which  he 
immediately  sank  into  sleep.  The  examination  of  the  blood 
showed  reds  4,500,000,  whites  13,000,  hemoglobin  80  per  cent. 
The  treatment  consisted  of  the  administration  of  strychnine, 
1-30  gr.  and  caffiein  sodium  benzoate  2  gr.,  given  hypodermically 
every  four  hours.  The  urine  at  this  time  was  light  amber  in 
color.  It  was  acid  in  reaction,  with  a  specific  gravity  of  1.015. 
There  was  a  slight  amount  of  albumin  present,  but  no  sugar  or 
casts.  Nourishment  consisted  of  six  ounces  of  milk  and  twelve 
ounces  of  water. 

Outcome. — On  the  third  day  consciousness  leturned.  The 
man  had  no  recollection  of  the  past  two  days.  He  complained  of 
a  slight  headache  and  dizziness.  His  face  had  a  peculiar  pinkish 
color,  but  the  color  of  the  hands  was  normal.  At  6  a.m.  his  tem- 
perature was  99.3°,  pulse  88,  respiration  24;  at  6  p.m.  his  temper- 
ature was  99.1°,  pulse  72,  respiration  28.  On  the  fourth  day  his 
general  appearance  was  good.  He  complained  of  no  discomfort 
and  was  taking  liquid  nourishment.  All  medication  had  been  dis- 
continued. The  urine  was  dark  amber  in  color,  was  acid  in  reac- 
tion, had  a  specific  gravity  of  1.025,  and  showed  no  albumin, 
sugar  or  casts.  At  6  a.m.  temperature  was  98.1°,  pulse  84,  res- 
piration 20;  at  6  p.m.  temperature  was  98.2°,  pulse  80,  respira- 
tion 22.  From  this  day  on  convalescence  continued  uneventful. 
The  man  was  discharged  well  on  the  seventh  day.  At  the  time 
of  discharge  the  blood  examination  showed  5,000,000  red  cells, 
10,000  whites  and  90  per  cent,  hemoglobin. 

REFERENCES. 

1  Landois :  Text-Book  of  Human  Physiology.  Ed.  10,  1905,  p.  58. 

2  Thompson,  W.  G. :  Tr.  Assn.  Am.  Phys.,  1902. 

3  Steele:  Philadelphia  Med.  Jour..  February  16,  1901. 

4  Brunneaux :  These  de  Paris,  1893. 

5  Finkelstein:  Lancet,  London,  1891,  ii,  3778. 


104  DANDRIDGE    MEMORIAL 

6  Scott,  A. :  EncVcl.  Jahrb.  d.  ges.  Heilk.,  1895,  vi 

7  Bruns :  Neurol.  Ccntralbl.,  1902,  No.  6,  p.  242. 

8  Pauski,  Alex. :  Neurol.  CentralbL,  1902,  No  6,  p.  242 

9  Becker:  Deutsche  med.  Woch.,  1893,  xix,  571. 

10  Bontecon:  Med.  News,  Troy,  N,  Y.,  1887. 

11  Broadbent:  St.  Mary's  Hosp.  Rep.,  London,  1893. 

12  Struthers :  Edinburgh  Med.  Jour.,  1855-6. 

13  Heinicke:  Deutsche  Chirurgie,  1885,  Part  18. 


UNEQUAL  PUPILS  AS  AiN  EARLY  SIGN  IN  PHTHISIS. 


BY  J,   L.  TUECilTER,   M.D. 


A  PUPILLARY  difference  as  a  phenomenon  in  unilateral  pulmo- 
nary tuberculosis  has  been  recognized  for  some  time,  still  we 
find  that  in  most  text-books  and  writings  upon  this  subject  it  re- 
ceives but  little  or  no  mention.  This  is  probably  due  to  the  fact 
that  this  difference  is  not  always  present  and  its  diagnostic  sig- 
nificance has  not  been  sufficiently  worked  out;  nevertheless, 
when  this  sign  can  be  elicited  it  carries  with  it  a  good  deal  of 
importance. 

In  examining  for  the  pupillary  difference  the  room  should 
be  only  moderately  light,  or  the  background  of  a  well-lighted 
room  may  be  used.  Direct  daylight  or  a  bright  artificial  light  ob- 
scures the  difference  because  of  an  existing  hypertonus  of  the 
sphincter  pupillse.  The  pupils  are  examined  in  the  ordinary  way 
by  covering  the  eyes  with  our  hands,  thus  relaxing  all  hypertonus, 
and  then  in  diffused  light,  quickly  watching  the  reaction.  If  there 
is  a  difference  you  will  note  that  the  one  pupil  is  dilated  more  than 
the  other,  and  that  it  reacts  less  completely  and  less  sluggishly.  In 
other  words,  it  seems  to  lag.  In  a  large  number  of  cases  it  is  not 
necessary  to  test  the  reaction  of  the  pupil,  but  the  diff^erence  can 
readily  be  noted  with  the  eyes  at  rest,  provided  again  the  light  be 
not  too  strong. 

In  a  large  majority  of  the  cases  in  which  the  sign  occurs  the 
pupil  is  wider  on  the  side  of  the  pulmonary  involvement,  and 
this  led  Geza  Fodor,  who  first  described  this  phenomenon,  to  the 
belief  that  the  reaction  is  due  to  a  stimulation  of  the  sympathetic 
nerve  fibers,  causing  on  that  side  a  spastic  mydriasis.  Neverthe- 
less, in  many  cases  the  opposite  is  true,  namely,  that  the  pupil  of 
the  unaft'ected  side  is  wider,  and  it  is  this  fact  which  led  many 
observers  to  discard  the  phenomenon  as  having  no  definite  value. 
It  remained  for  Leo  Wolfer  to  determine  the  real  cause  of  the 
pupillary  difference.  He  came  to  the  conclusion  that  the  widen- 
ing of  the  pupil  is  due  to  a  stimulation  of  the  sympathetic  fibers 

105 


106  D  A  N  D  R  I  D  G  E    iJ  E  U  O  R  1  A  L 

caused  by  pressure  exerted  b}^  enlarged  bronchial  glands  of  that 
side.  For  this  reason  it  is  not  necessarily  observed  in  the  pupil 
corresponding  to  where  our  objective  findings  lead  us  to  locate 
the  pulmonary  process,  in  so  far  as  the  glands  on  this  side  are 
not  invariably  and  of  necessity  sufficiently  enlarged  to  stimulate 
the  corresponding  sympathetic  fibers. 

After  observing  a  large  series  of  cases  I  have  been  able  to 
substantiate  these  later  findings,  and  am  satisfied  that  a  compar- 
ative dilatation  of  one  pupil  signifies  an  enlargement  of  the  bron- 
chial lymph  glands  of  the  corresponding  side.  y\s  such  glandular 
involvement  is  usually  tubercular  in  character,  and  takes  place 
at  a  time  when  the  lung  itself  does  not  as  yet  show  destructive 
changes,  I  feel  that  this  sign  is  most  valuable  in  the  early  diag- 
nosis of  pulmonary  tuberculosis.  Before  drawing  a  definite  con- 
clusion as  to  the  significance  of  this  phenomenon,  it  is  of  course 
necessar}'-  to  rule  out  affections  of  the  eye  which  may  cause  pu- 
pillary differences,  as  well  as  certain  conditions  of  the  thorax, 
such  as  tumor  or  aneurism. 

Several  case  reports  may  serve  to  show  the  value  of  this  pu- 
pillary difference  when  observed. 

A  young  man,  twenty-five  years  of  age,  occupation  bank  clerk, 
consulted  me  because  of  a  lang-standing  stomach  trouble,  which 
would  clear  up  at  times  and  then  return.  While  examining  the 
patient  I  noticed  the  inequality  of  his  pupils,  the  right  being 
wider  than  the  left  and  reacting  more  sluggishly.  In  view  of  the 
fact  that  there  was  a  marked  tubercular  famil}'-  history,  I  made 
a  chest  examination,  but  found  nothing,  nor  did  he  have  any 
other  subjective  symptoms  which  might  indicate  a  pulmonary 
trouble.  The  stomach  condition  persisted  for  two  months,  and 
gradually  cleared  up  after  sending  him  away  on  his  summer  -^^a- 
cation  with  strict  injunctions  as  to  rest.  He  returned  to  me 
several  months  later,  greatly  worried  over  the  fact  that  he  had 
had  a  very  slight  hemorrhage,  and  for  two  subsequent  days  his 
sputum  was  tinged  with  blood.  On  chest  examination  I  was 
able  to  find  a  very  early  involvement  of  the  right  apex, 

A  young  patient,  twenty-eight  years  of  age,  with  an  early 
tuberculosis  involving  the  left  apex,  has  been  under  my  care  for 
several  months.  He  is  tmder  tuberculin  treatment,  so  I  have 
the  opportunity  of  seeing  him  twice  a  week  and  examining  him 
frequently.  This  man  shows  a  dilatation  of  the  right  pupil — in 
other  words,  not  on  the  corresponding  side  of  the  lesion.  Even 
though  the  examination  for  dulness  on  either  side  of  the  spine 


T  U  E  C  H  T  E  R  107 

gives  us  rather  doubtful  results  in  the  adult,  because  of  the  nor- 
mal dulness  over  this  area,  nevertheless,  in  so  far  as  this  patient 
was  not  very  muscular,  1  felt  that  I  was  able  to  elicit  a  more  or 
less  localized  area  of  dulness  over  the  right  side.  An  X-ray  ex- 
amination of  this  case  confirmed  these  findings,  and  showed  an 
involvement  of  the  left  apex,  together  with  an  enlarged  glandu- 
lar mass  about  the  size  of  a  pigeon's  egg  at  the  right  hilum, 
which  accounted  for  the  pupillary  enlargement. 

A  young  girl  of  eighteen  years  presented  the  various  subjec- 
tive tubercular  symptoms,  such  as  decreasing  strength,  shortness 
of  breath  on  exertion,  subnormal  temperature  in  the  morning, 
together  wath  a  rapid  pulse  and  afternoon  rise  of  temperature. 
There  was  a  dilatation  and  sluggishness  of  the  left  pupil.  The 
chest  examination  was  at  first  negative,  except  for  increased 
muscular  rigidity  over  the  left  apex.  About  a  month  later  I  was 
able  to  elicit  crepitation  over  this  area.  I  had  the  opportunity  to 
have  an  X-ray  examination  made  and  it  showed  a  marked  infil- 
tration about  the  left  hilum  sufficient  to  cause  pressure  on  the 
sympathetic  of  that  side. 

This  phenomenon,  if  we  look  for  it,  can  very  frequently  be 
found  in  tuberculosis  of  the  bronchial  lymph  glands  in  children. 
It  forms  a  valuable  point  in  diagnosis  in  that  type  of  the  disease 
where  the  onset  is  insidious  and  where  the  child  has  not  yet  ac- 
quired the  characteristic  paroxysmal  attacks  of  cough.  An  in- 
teresting case  of  this  kind  came  under  my  observation  on  my 
service  in  the  children's  ward  of  the  Ohio  Maternity  Hospital. 
A  child,  two  and  a  half  years  old,  had  been  exposed  before  ad- 
mission, to  a  tuberculous  mother.  The  child  passed  almost  im- 
perceptibly from  a  condition  of  health  to  one  of  disease.  The 
appetite  became  poor,  the  cheeks  pale  and  there  was  an  apparent 
loss  of  flesh.  Irregular  pyrexia  pointed  to  some  systemic  affec- 
tion, but  examination  disclosed  nothing.  The  child  began  to 
cough  very  slightly,  and  a  Pirquet  skin  reaction  was  markedly 
positive  at  the  end  of  twent)'-four  hours,  which  at  this  age  meant 
that  we  were  dealing  wath  an  active  tuberculosis  somewhere  in 
the  body.  There  was  a  marked  dilatation  and  lagging  of  the 
left  pupil,  and  I  made  a  diagnosis  of  tuberculosis  of  the  tracheal, 
bronchial  and  pulm.onary  l}-mph  glands.  The  child  was  placed 
out  of  doors  and  did  fairly  well,  but  later  developed  a  severe 
ulcerative  enteritis  which  proved  fatal.  The  autopsy  showed, 
besides  the  ulcerative  condition  of  the  bowel,  a  marked  enlarge- 


108  DANDRIDGE    MEMORIAL 

ment  of  the  lymph  glands  around  the  left  hiluni  and  bronchus. 
The  lungs  were  not  involved. 

These  cases  serve  to  illustrate  that  a  pupillary  difference, 
which  is  not  caused  by  a  pathological  condition  of  the  eye,  forms 
a  valuable  early  sign  in  phthisis,  both  in  the  absence  of  other 
signs  and  symptoms,  as  well  as  in  their  presence.  It  is  not  nec- 
essarily found  on  the  side  corresponding  to  the  pulmonary  in- 
volvement, in  so  far  as  it  is  due  to  pressure  on  the  sympathetic 
by  enlarged  bronchial  lymph  glands. 


ACUTE  TUBERCULOUS  ENDAORTITIS.* 


BY    PAUL    G.    WOOLLEY.    M.D. 


The  present  consensus  of  opinion  is  to  the  effect  that  tubercle 
bacilli  cannot,  except  in  the  rarest  instances,  be  observed  in  the 
circulating  blood.  Yet  we  know  that  they  must  be  present  there 
and  often  in  large  numbers.  We  have  built  up  our  ideas  of  the 
production  of  miliary  tuberculosis  upon  the  assumption  that  the 
organisms  that  cause  the  disease  are  distributed  by  the  blood,  to 
which  they  gain  access  in  three  ways ;  by  rupture  of  a  tuberculous 
focus  in  one  or  another  organ  into  a  blood  vessel ;  by  the  invasion 
of  the  walls  of  blood  vessels,  especially  veins,  by  the  tuberculous 
process,  with  the  production  of  a  tuberculous  lesion  in  the  intima 
of  the  vessel  from  which  the  bacilli  are  distributed ;  and  by  the 
involvement  of  the  thoracic  duct  in  a  tuberculous  process,  from 
foci  in  which  tubercle  bacilli  gain  access  to  the  venous  blood. 

Vascular  involvement  is  frequent,  and  it  is  probable  that  a 
search  in  every  case  of  miliary  tuberculosis  will  be  rewarded 
by  finding  a  focus  of  extension,  most  frequently  in  the  smaller 
pulmonary  veins,  or  thoracic  duct,  less  frequently  in  the  renal 
or  pulmonary  arteries,  aorta,  or  the  vessels  of  one  or  another 
organ  of  the  body. 

Invasion  per  extensionejn  is  the  rule  in  small  vessels.  It  is 
not  so  common  in  large  ones,  nor  indeed  is  vascular  involvement 
of  any  sort.  This  invasive  process  is  the  one  that  usually  accounts 
for  the  production  of  a  generalized  tuberculosis.  It  is  the  process 
by  which  the  bacilli  gain  entrance  to  the  blood  stream,  whence 
they  are  distributed.  But  there  is  a  second  process  by  which  the 
secondary  vascular  lesions  are  produced.  It  may  be  assumed  to 
occur  generally  as  the  result  of  thrombosis  of,  or  endothelial 
phagocytosis  in,  the  capillaries  of  the  tissues.  As  a  result  of 
either,  the  vessel  wall  is  involved  from  the  side  of  the  intima. 
This  invasion  from  the  lumen  is  frequent  in  small  vessels,  but  is 

*  From  the  Johns  Hopkins  Hospital  Bulletin,  vol.  xxii,  No.  240,  March. 
1911. 

109 


110  DANDRIDGE    MEMORIAL 

infrequent  in  large  ones  for  obvious  reasons.  It  is  least  common 
in  the  aorta, 

A  review  of  the  literature  on  tuberculosis  reveals  the  fact 
that  aortic  lesions  may  be  of  the  invasive  or  of  the  metastatic 
type,  and  that  both  are  rare.  The  metastatic  lesions  may  be  acute 
or  chronic  in  character. 

In  the  cases  of  Dittrich  and  Kamen  the  aorta  was  involved 
from  adherent  tuberculous  bronchial  glands,  and  this  was  fol- 
lowed by  acute  miliary  tuberculosis  and  rupture  of  the  aorta 
(Kamen).  In  Buttermilch's  case  the  aortic  involvement  was 
secondary  to  a  vertebral  tuberculosis. 

Srhmorl  mentions  two  cases  of  acute  miliary  tuberculosis 
which  he  conceives  as  being  the  result  of  the  perforation  of  a 
tuberculous  lymph  gland  or  of  a  pulmonary  cavern  into  the  aorta. 

Examples  of  tuberculous  aortitis  by  extension  are  the  cases  of 
Dittrich.  Kamen,  Schmorl,  Hanau  and  Sigg,  and  Buttermilch. 
In  the  case  of  Hanau  and  Sigg  an  aneurism  ruptured  into  a 
cavern  in  the  lung.  It  is  entirely  probable  that  the  aorta  was 
weakened,  its  walls  infiltrated  and  an  aneurism  caused  thereby, 
after  which  rupture  occurred,  for  the  edges  of  the  torn  wall  of 
the  aneurismal  sac  showed  tuberculous  vegetations. 

The  chronic  type  of  tuberculous  endaortitis  is  illustrated 
by  the  cases  of  Forssner,  Benda,  Aschoff,  Longcope,  Schmorl, 
Gaylord,  Simnitsky  and  Luksch. 

In  this  series  there  has  been,  with  few  exceptions,  a  more  or 
less  severe  arteritis  or  arteriosclerosis  in  association  with  the 
tuberculous  changes,  a  coincidence  that  has  lead  to  the  assump- 
tion that  the  specific  lesions  have  been  the  result  of  invasion  of 
parietal  thrombi  by  tubercle  bacilli.  In  them  the  process  has 
apparently  shown  no  tendency  to  advance  along  the  intima,  so 
that  the  lesions  have  increased  into  the  lumen  producing  either 
flattened  nodules  or,  more  commonly,  polypoid  growths.  In  all 
the  cases  reported  by  Benda  the  lesions  were  polypoid.  In  two 
cases  they  were  situated  upon  areas  of  sclerosis,  in  a  third  upon 
an  atheromatous  ulcer.  In  Luksch's  case  the  lesions  in  the  aorta, 
anonyma,  and  left  subclavian  were  upon  an  endarteritic  basis. 
In  Forssner's  case  there  was  no  arteriosclerotic  change,  but  it  is 
possible  that  in  this  the  lesion  was  primary  in  the  media  resulting 


WOOLLEY  111 

from  a  primarj'^  involvement  of  one  of  the  vasa  vasorum.  The 
intimal  tubercle  measured  4x1  cm.  Stroebes'  case  was  one  of 
a  child  in  which  there  was  a  polypoid  growth  7  mm.  high  and 
3-4  mm.  thick,  with  no  arteriosclerosis.  Aschoff's  case  showed 
extreme  arteriosclerosis  and  a  tuberculous  mass  the  size  of  a  bean 
near  the  origin  of  the  ductus  Botalli.  The  lesion  described  by 
Longcope  was  a  polyp  3  cm.  long,  which  was  found  in  the 
descending  aorta  of  a  child  sufifering  from  tuberculous  hip  dis- 
ease. The  report  of  Simnitsky,  to  which  I  have  not  had  access, 
save  through  Forssner"s  paper,  concerned  itself  with  a  case  of 
chronic  pulmonary  and  intestinal  tuberculosis,  and  no  miliary 
tuberculosis.  The  aortic  lesion  was  in  one  of  the  sinuses  of 
Valsalva. 

In  all  of  Schmorl's  five  cases  there  was  arteriosclerosis,  and 
in  all  the  cases  the  tuberculous  polypi  were  situated  upon 
atheromatous  ulcers. 

Accordingly  it  appears  that  in  this  chronic  group  arterio- 
sclerosis is  more  frequently  present  than  is  natural  in  tuber- 
culosis, a  disease  in  which  the  arterial  tree  is  not  as  a  rule  severely 
affected,  and  it  is  therefore  quite  possible  that  the  conception 
that  the  aortic  lesions  are  the  result  of  infection  of  mural  thrombi 
is  corref't  in  the  majority  of  cases.  Ten  of  fourteen  of  the 
reported  cases  showed  the  presence  of  arteriosclerosis.  In  two 
cases  I  have  not  been  able  to  find  a  description  of  the  general 
aortic  condition  (Gaylord  and  Simnitsky)  and  in  two  the  patients 
were  young  individuals  (Longcope  and  Stroebe).  In  this 
enumeration  Forssner's  case  is  excepted,  since  it  is  possibly  in  a 
class  by  itself. 

The  series  of  acute  tuberculous  endaortitis  include  the  cases 
of  Marchand.  Iluber,  Schuchardt,  Hanot,  Hanot  and  Levi, 
Simnitsky,  Blumer,  Flexner  and  the  one  to  be  reported  in  this 
paper.  In  all  of  these  miliary  tubercles  were  present  in  the 
intima  of  the  aorta. 

The  cases  of  Marchand  and  Huber  were  merely  mentioned 
by  Weigert  who  described  them  as  showing  the  most  exquisite 
structure,  "giant  cells,  caseated  center,  etc."  Schuchardt  reported 
minute  lesions  situated  near  the  junction  of  the  thoracic  and 
abdominal  aorta.    There  was  verv  little  arteriosclerosis.     I  have 


112  DANDRIDGE    MEMORIAL 

been  unable  to  find  the  report  of  the  cases  of  Hanot  and  Sini- 
nitsky.  That  of  Hanot  and  Levy  was  one  in  which  a  tubercle 
was  found  in  the  superior  portion  of  the  thoracic  aorta.  The 
tubercle  discovered  by  Flexner  was  situated  about  2.5  cm.  below 
the  left  subclavian  artery,  and  measured  2.5  x  1  mm.  in  diameter. 
The  aorta  was  not  sclerotic.  Flexner  believed  that  this  tubercle 
was  secondary  to  an  infective  thrombus  in  the  pulmonary  artery. 

In  all  of  the  cases,  of  either  acute  or  chronic  type,  the  lesions 
have  been  described  as  containing  large  numbers  of  tubercle 
bacilli,  a  fact  that  has  an  important  bearing  upon  the  manner  of 
the  production  of  the  general  miliary  tuberculosis  that  has  been 
present  in  all  except  Simnitsky's  first  case,  for  many  writers 
believe  that  the  general  lesions  are  the  result  of  the  escape  of 
bacilli  from  the  aortic  lesions.  It  would  seem  reasonable,  how- 
ever, to  limit  the  production  of  secondary  general  disease  to  the 
chronic  cases,  for  in  the  acute  ones  the  aortic  lesions  seem  rather 
to  be  a  part  than  the  cause  of  it. 

The  case  that  I  wish  to  report  falls  in  the  category  of  acute 
tuberculous  endaortitides. 

Case  152173. — The  patient,  a  man  of  fifty-nine  years,  and  a 
laborer,  was  admitted  to  the  Cincinnati  Hospital  on  November  11. 
1909,  complaining  of  "bladder  trouble."  In  August,  1909,  he  had 
been  admitted  to  a  hospital  for  cystitis,  which  was  improved  by 
treatment  with  urotropin  and  irrigations.  He  had  suffered  with 
"bladder  trouble"  for  some  two  years  previously,  that  is  to  say, 
he  had  had  pain  on  micturition,  a  symptom  which  was  not  con- 
stant, but  which  occurred  in  exacerbations,  at  the  onset  of  each 
of  which  he  passed  some  blood.  At  the  time  of  his  last  admission 
he  gave  no  evidence  of  pulmonary  or  cardio-vascular  disease,  ex- 
cept a  slight  roughening  of  the  breath  sounds  during  expiration. 
There  was  no  splenic  or  hepatic  enlargement.  He  suffered  with 
involuntary  urination  accompanied  by  pain.  The  urine  was  dark 
red  and  contained  blood  clots. 

A  week  after  admission  he  had  a  convulsion  at  9  p.m.,  accom- 
panied by  a  rise  of  temperature  to  102°  F.,  and  complained  of 
pain  radiating  from  the  bladder  to  the  renal  region.  There  was 
pain  and  tenderness  in  left  lumbar  region.  Subsequently  the 
temperature  showed  an  eveninrr  rise.  Blood  examinations  showed 
a  leuccpenia,  the  counts  varving  from  4400  to  7800.  A  cysto- 
scopic  examination  showed  that  there  was  a  severe  cvstitis  pres- 
ent. The  capacity  of  the  bladder  was  but  90  cc.  A  diagnosis  of 
"cystitis,  probably  tuberculous,  secondary  to  tuberculosis  of  kid- 


WOOLLEY  113 

ney,"  was  made.  On  December  10,  complaint  was  made  of  ab- 
dominal pain,  and  on  December  12  death  occurred.  The  post 
mortem  was  made  three  hours  after  death. 

Briefly  stated  the  result  of  the  autopsy  was  that  a  generalized 
acute  miliary  tuberculosis  involving  the  lungs,  spleen,  liver,  peri- 
bronchial and  mesenteric  lymph  glands,  kidneys,  adrenals,  pan- 
creas and  aorta  was  found.  The  bladder  and  kidneys  showed 
both  chronic  and  acute  tuberculous  changes. 

In  the  thoracic  part  of  the  aorta  there  were  a  few  fatty 
streaks,  and  at  the  beginning  of  the  descending  arch  there  was 
one  calcified  plaque.  The  abdominal  aorta  showed  an  almost 
completely  healthy  appearance  except  at  a  Doint  10-15  cm.  above 
the  bifurcation,  at  which  point  were  two  small  raised  areas  on  the 
intima  that  had  the  appearance  of  recent  vegetations  and  which 
measured  about  a  millimeter  in  diameter.  There  was  no  tuber- 
culous focus  in  the  vicinity  of  the  aorta  in  the  neighborhood  of 
these  nodules. 

Microscopic  examination  of  the  vegetation-like  nodules  in  the 
aorta  shovved  that  they  were  really  intimal  tubercles,  composed 
of  epithelioid  and  small  round  cells,  a  partial  endothelial  covering, 
and  a  central  area  of  caseation.  In  them  were  large  numbers 
of  acid-fast  rods  of  typical  and  atypical  form,  but  no  giant  cells. 
Beneath  these  tubercles  the  media  and  adventitia  were  apparently 
normal,  except  immediately  in  the  base  of  the  tubercles  where 
there  was  evidence  of  a  minimal  degree  of  degeneration  in  the 
adjacent  part  of  the  media. 

In  the  lesions  I  have  studied  the  bacilli  were  more  numerous  in 
the  peripheral  parts,  and  several  were  observed  in  the  immediate 
vicinity  of  the  lumen  of  the  vessel.  It  is  possible  that  some  had 
entered  the  blood  stream,  but  not  in  sufficient  numbers  to  cause 
the  appearance  of  the  myriad  lesions  in  other  organs. 

A  further  observation  of  some  interest  relates  to  the  form  of 
the  bacilli  in  the  intimal  tubercles.  In  the  cases  in  the  literature,  I 
have  not  been  able  to  find  reference  to  any  other  than  presumably 
typical  rods.  In  my  case,  however,  many  of  the  rods  were  far 
from  typical.  Quite  a  large  proportion  were  of  irregular  form, 
and  while  no  actually  branchin?"  ones  could  be  found,  some  of 
them  showed  bizarre  figures  that  suggested  branching. 

I  believe  that  in  this  case  the  generalized  miliary  tuberculosis, 
of  which  the  aortic  lesions  were  a  part,  was  the  result  of  dis- 
tribution of  the  organism  from  the  older  foci  in  the  kidney,  and 
that  it  did  not  result  from  distribution  of  tubercle  bacilli  from 
the  aortic  tubercles.  The  case  therefore  belongs  logically  with 
the  group  of  acute  heniatogenous  aortitides. 

It  is  difficult  to  account  for  the  lodgment  of  the  organism  in 
these  acute  cases  unless  one  presupposes  at  least  an  incipient  de- 


114  DANDRIDGE    MEMORIAL 

generation  of  the  cells  of  the  intinia,  and  the  formation  of  ever  so 
little  fibrin  in  which  the  bacilli  may  become  entangled.  It  is  very 
possible  that  in  all  cases  of  general  infection  and  toxemia,  more 
damage  is  done  to  the  endoi-helial  lining  of  the  blood-vessels  than 
we  can  readily  appreciate,  a  possibility  which  Baldassari  has 
shown  to  exist  by  his  observations  on  the  endocardium  in  cases  of 
infection  and  intoxication.  Certainly  it  seems  simpler  to  look  at 
the  process  in  this  way  than  to  suspect  that  normal  endothelial 
cells  in  the  aorta  are  fortunate  enough  to  be  able  to  seize  single 
organisms  from  the  rapidly  flowing  stream  of  blood  that  passes 
them. 

CONCLUSIONS. 

1.  The  case  here  reported  is  the  eleventh  of  acute  tuberculous 
endaortitis. 

2.  The  aortic  tubercles  were  the  result  not  of  extension,  but 
of  metastasis  from  chronic  lesions  in  the  kidney. 

3.  The  general  miliar)^  tuberculosis  that  co-existed  with  the 
chronic  tuberculosis,  was  not  the  result  of  dissemination  of 
organisms  from  the  aortic  lesions. 

4.  The  bacilli  in  the  aortic  lesions  showed  bizarre  forms  with 
a  tendency  to  branching. 

RliFKRENCES. 

Longcope :  Johns  Hopkins  Hosp.  Bull.,  1901. 
Benda :  Lubarsch  u.  Ostertag's  Ergebnisse,  1899. 

:  Berl.  klin.  Woch.,  1899. 

Blumer:  Am.  Jour.  Med.  Sci.,  1899;  Albany  Med.  Ann.,  1899. 
Schmorl :  Munch,  mcd.  Woch.,  1902. 
Luksch:  Centralbl.  f.  allg.  Path.,  1904  (Ref.). 
Forssner:  Ibid.,  1905  (Lit). 
Simnitsky:   (Cited  by  Forssner.) 

Gaylord :  Allbutt's  System  of  Medicine,  1909  (cited  by  Forssner  and 
Longcooe). 

Schuchardt:  Virchow's  Archiv,  1882. 

Marchand :  Cited  by  Weigert.     Virchow's  Archiv,  Ixxxviii. 

Huber :  Cited  by  W'eigert.     Virchow's  Archiv,  Ixxxviii. 

Hanot :  Senu.  med.,  1895. 

Hanot  et  Levy:  Arch,  de  mcd.  exh.,  1896. 

Flexner :  Johns  Hopkins  Hosp.  Bull..  1891. 

Stroebe:  Centralbl.  f.  allg.  Path.,  1897. 

Aschoff:  Vcrhandl.  d.  Deutsche  path.  Gesellsch,  1899. 

Buttermilch :  Lubarch  und  Ostertag's  Ergebnisse,  vi. 

Kamen :  Ziegler's  Beitrage,  xvii. 

Dittrich :  Cited  bv  Blumer. 

Hanau  u.  Sigg:  Lubarsch  u.  Ostertag's  Ergebnisse,  v. 

Baldassari:  Centralbl.  f.  allg.  Path.,  1909. 


THE   FUNCTION   OF   THE   CHOROID   PLEXUSES   OF 
THE  CEREBRAL  VENTRICLES  AND  ITS  RELA- 
TION TO  THAT  OF  THE  PITUITARY  GLAND.* 


BY    SIMON    PENDLETON    KRAMER,    M.D. 


The  secretory  organs  for  the  cerebro-spinal  fluid  are  the  choroid 
plexuses  of  the  third,  fourth  and  lateral  ventricles.  These  are 
highly  vascular  projections  of  the  pia  mater  into  the  ventricles, 
covered  with  villous-like  projections  about  1  to  2  mm.  in  diameter. 
Under  the  microscope  these  villi  are  seen  to  be  made  up  of  a 
number  of  secondary'-  villi  about  0.25  mm.  in  diameter,  which 
again  show  grape-like  projections.  Through  the  center  of  the 
villi  run  comparatively  thick-walled  blood  vessels,  giving  the 
entire  organ  a  highly  vascular  appearance.  The  connective  tissue 
of  the  villi  is  that  of  the  pia  mater.  Covering  the  villi  of  the 
plexuses  is  a  layer  of  large  spheroidal  cells,  in  each  of  which  may 
be  seen,  in  addition  to  the  nucleus,  yellowish  granules.  These 
cells  are  probably  the  secretory  cells  of  the  organ.  The  appear- 
ance of  the  plexuses  strongly  suggests  an  inverted  gland  which, 
instead  of  pouring  its  secretion  into  a  series  of  ducts,  empties 
directly  into  the  ventricular  system  of  the  brain. 

If  one  strip  the  choroid  plexuses  from  both  the  lateral  ven- 
tricles of  a  dog  recently  killed  by  bleeding,  and  rubs  them  up 
in  2  c.c.  of  normal  saline  solution  and  injects  the  filtrate  into 
the  jugular  vein  of  another  dog,  it  will  be  found  that  this  extract 
causes  a  marked  fall  in  the  blood  pressure.  This  effect  was 
found  to  be  constant  in  ten  experiments. 

Figure  1  is  from  a  tracing  of  such  an  experiment.  The 
blood  pressure  was  obtained  by  connecting  the  carotid  or  femoral 
artery  of  the  animal  with  a  mercury  manometer.  The  respira- 
tions were  recorded  by  means  of  a  Paul  Bert  pneumograph 
connected  with  a  Marey  tambour,  so  arranged  that  the  up-stroke 
represents  inspiration,  the  down-stroke  expiration.    The  time  of 

*  Reprinted  from  The  Journal  of  the  American  Medical  Association, 
January  28,  1911,  vol.  Ivi,  pp.  265-268. 

115 


116  DANDRIDGE    MEMORIAL 

injection  was  recorded  by  an  electric  signal.  The  injection  was 
made  into  the  jugular  vein.  In  all  experiments  the  animals  were 
under  light  ether  anesthesia  administered  through  a  tracheal  tube. 
This  animal  received  1  c.c,  or  half  the  total  extract  made  from 
the  choroid  plexuses  of  the  lateral  ventricles  of  another  dog 
killed  by  bleeding.  The  drop  in  blood  pressure,  which  in  this 
experiment  was  preceded  by  a  slight  momentary  rise  (not  con- 
stant), began  fifteen  seconds  after  the  beginning  of  the  injection, 
reached  its  maximum  (that  is,  50  mm.)  twenty-eight  seconds 
after  the  beginning  of  the  injection,  and  returned  to  within  5  mm. 
of  the  original  pressure  in  two  minutes  and  twenty-five  seconds. 
The  rate  of  the  heart-beat  was  apparently  unchanged.  The  res- 
piration was  increased  in  rhythm  from  40  to  60  per  minute. 
Extracts  made  from  the  choroid  plexuses  of  the  human  brain 
show  the  same  effects  in  even  smaller  doses. 

Figure  2  is  a  tracing  obtained  by  injecting  into  the  jugular 
vein  of  a  dog  1  c.c.  of  an  extract  made  by  rubbing  up  the  plexus 
from  one  lateral  ventricle  in  10  c.c.  of  normal  saline  solution. 
The  brain  was  removed  from  a  man,  thirty-five  years  of  age,  five 
and  one-half  hours  after  death  from  pneumonia. 

Extracts  made  from  the  choroid  plexus  of  the  fourth  ventricle 
produce  the  same  reaction. 

The  reaction  exhibited  in  Figure  3  is  independent  of  the 
action  of  the  vagus  nerves,  since  the  same  effect  is  obtained  when 
both  vagus  nerves  have  been  divided. 

The  thought  suggested  itself  that  possibly  in  certain  cerebral 
affections,  particularly  in  such  as  were  associated  with  hyper- 
secretion of  the  cerebro-spinal  fluid,  the  fluid  might  contain  an 
excess  of  this  depressant  evidently  secreted  by  the  choroid  plex- 
uses. Accordingly  experiments  were  made  with  cerebro-spinal 
fluid  obtained  by  lumbar  puncture  in  three  such  cases. 

Figure  4  is  a  tracing  obtained  from  a  dog  into  whose  jugular 
vein  were  injected  12  c.c.  of  cerebro-spinal  fluid  obtained  by 
lumbar  puncture  from  a  patient  with  edema  of  the  brain  follow- 
ing a  blow  on  the  head  producing  subtentorial  hemorrhage.  It 
will  be  seen  that  the  injection  caused  a  marked  (55  mm.)  and 
prolonged  fall  in  blood  pressure,  followed  by  an  exceedingly 
slow  and  incomplete  recovery.     The  cerebro-spinal  fluid  in  this 


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KRAMER  117 

case  evidently  contained  a  great  excess  of  the  "choroid  de- 
pressant." 

Figure  5  is  a  tracing  obtained  from  a  dog  into  whose  jugular 
vein  were  injected  5  c.c.  of  cerebro-spinal  fluid  drawn  from  a 
marked  case  of  delirium  tremens.  This  fluid  was  much  more 
depressant  than  that  from  the  previous  case. 

The  injection  of  10  c.c.  of  the  same  fluid  fifteen  minutes  later 
into  the  same  dog  produced  a  most  violent  and  prolonged  de- 
pression, from  which  the  animal  incompletely  recovered  only 
after  an  interval  of  eight  minutes.    This  is  shown  in  Figure  6. 

Figure  7  is  a  tracing  obtained  by  injecting  30  c.c.  of  cerebro- 
spinal fluid  drawn  from  a  subject  who  had  recovered  from  de- 
lirium tremens.  There  was  but  little  depressant  effect,  a  fall  in 
blood  pressure  of  not  more  than  5  mm.,  whi^'h  was  quickly  re- 
covered. The  individual  from  whom  this  cerebro-spinal  fluid 
was  obtained  had  had  a  mild  attack  of  delirium  tremens  which 
had  lasted  only  forty-eight  hours,  and,  at  the  time  the  fluid  was 
withdrawn,  the  patient's  pulse  was  normal  again  and  the  attack 
of  delirium  tremens  had  disappeared. 

The  patient  died  from  whom  the  fluid  used  in  Experiments 
5  and  6  was  obtained,  and  at  autopsy  a  marked  cerebral  edema 
was  found.  The  ventricles  were  filled  with  fluid  which,  when 
injected  into  dogs,  was  markedly  depressant. 

It  also  occurred  to  me  that  if  such  a  depressant  were  secreted 
by  the  choroid  plexuses  and  poured  out  into  the  ventricular 
system  it  would  meet  there  whatever  was  given  oflF  by  the  pitu- 
itary body,  and  it  seemed  wise  to  determine,  if  possible,  what 
action  these  two  principles  might  have  on  each  other.  As  has 
been  abundantly  shown,  the  infundibular  lobe  of  the  pituitary 
gland  contains  a  substance  which  causes  a  marked  elevation  in 
blood  pressure  lasting  for  some  time  and  accompanied  by  a 
marked  slowing  of  the  heart  and  an  increase  in  the  force  of  the 
cardiac  systole. 

Tracing  8  was  obtained  from  a  dog  into  whose  jugular  vein 
was  injected  0.75  c.c.  of  an  extract  of  the  infundibular  lobe  of 
the  sheeps'  pituitary  gland.  The  well-known  efiFect  is  here  nicely 
shown. 

When  an  injection  was  made  of  a  mixture  of  the  pituitary 


118  DANDRIDGE    MEMORIAL 

extract  just  mentioned  and  an  extract  of  the  human  choroid 
plexus  it  was  found  that  these  substances  tend  to  counteract  each 
other,  though  incompletely.  Of  course,  it  is  difficult  to  determine 
the  completeness  or  incompleteness  of  such  counteraction  in  the 
absence  of  known  dosage. 

If  we  examine  a  tracing  (Figure  9)  of  such  an  experiment  we 
shall  find  it  very  interesting.  The  depressant  effect  of  the  choroid 
is  shown,  but  lessened  in  amount  and  only  transitory  in  time. 
This  is  succeeded  by  a  rise  in  pressure  due  to  the  pituitary  ex- 
tract but  this  also  is  lessened  in  amount  (15  mm.)  and  greatly 
shortened  in  time  of  duration.  At  the  end  of  two  minutes  and 
thirty  seconds  the  blood  pressure  was  within  5  mm.  of  that  which 
obtained  before  the  injection.  The  slowing  of  the  heart  is 
present  but  also  reduced.  It  is  evident  then  that  these  two 
principles  which,  we  presume,  are  poured  into  the  cerebro-spinal 
fluid  have  a  tendency  to  counteract  each  other  insofar  as  their 
effect  on  the  circulatory  apparatus  is  concerned.  It  will  be  a 
matter  for  future  investigation  to  determine,  if  possible,  under 
what  circum.stances  the  one  or  the  other  gains  the  supremacy. 

A  further  report  on  the  nature  of  the  choroid  "depressant" 
will  also  be  made  in  the  future. 


THE  EFFECT  OF  INJECTIONS  OF  INDOL  AND 
TYROSIN  IN  EXPERIMENTAL  ANIMALS. 

A  Preliminary  Report.* 


BY   PAUL  G.    WOOLLEY,    M.D.^   AND   L.    H.    NEWBURGII,    M.D. 


During  the  past  year  we  commenced  a  series  of  experiments  on 
rabbits  and  white  rats,  the  object  of  which  was  to  discover  what 
relation  chronic  intoxications  wath  some  of  the  lower  derivatives 
of  protein  decomposition  bore  to  changes  in  the  adrenals  and  kid- 
neys. We  had  a  suspicion  that  indol  might  have,  in  the  process 
of  secretion,  or  in  the  process  of  transformation  into  indican,  or 
both,  an  effect  in  producing  changes  in  the  organs,  which  would 
indicate  hyperactivity  of  certain  organs  (the  liver,  and  perhaps 
the  adrenals)  or  irritative  changes  in  others  (the  kidneys).  There 
seemed  to  be  some  basis  for  this  suspicion  in  the  fact  that  indi- 
canuria,  especially  when  it  is  of  well-marked  degree,  is  accom- 
panied by  albuminuria  and  cylindruria.  It  seemed  useful  to  dis- 
cover, therefore,  whether  injections  of  indol  would  produce  any 
noticeable  changes  in  the  kidneys;  and,  since  the  liver  has  been 
supposed  to  be  the  site  of  transformation  into  indican,  it  seemed 
possible  that  some  changes  in  that  organ  might  be  expected.  The 
tyrosin  series  had  a  different  basis.  We  were  interested  in  the 
physiology  of  the  adrenal  glands,  and  had  been  led  to  suspect 
that  the  pigmentation  of  Addison's  disease  might  be  a  result  of 
variation  in  either  the  content  of  the  chromaffin  tissues  in  tyro- 
sinase, or  in  the  overabundance  of  tyrosin  or  some  related  sub- 
stance in  the  body.  This  was  indicated  by  the  suggestion  of 
von  Fiirth  that  melanin  and  related  bodies  are  the  result  of  the 
action  of  tyrosinase  or  related  oxydases  on  the  aromatic  constit- 
uents of  the  protein  molecule,  a  suggestion  which,  as  Adami  says, 
has  been  supported  by  Halle,  who  demonstrated  that  tyrosin  is 
converted  into  epinephrin  by  a  ferment  in  the  adrenal.     Adami 

*  From   The  Journal  of  the  American  Medical  Association,  June  17, 
1911,  vol.  Ivi,  pp.  1796  and  1797. 

119 


120  DAN  BRIDGE    MEMORIAL 

suggests  that  pigmentation  in  Addison's  disease  is  produced  when 
this  ferment  is  deficient — when,  in  other  words,  the  tyrosin  is  not 
converted  into  epinephrin  by  the  adrenal,  but  into  melanin  in  the 
skin.  All  of  which  induced  us  to  attempt  to  discover  whether 
tyrosin  would  stimulate  the  adrenals  to  increased  activity,  or 
whether  large  excesses  of  tyrosin  would  produce  melanosis  in  ex- 
perimental animals.  If  the  former  were  the  case,  we  might  ex- 
pect to  find  as  a  result  of  increased  epinephrin  production  either 
arterial  changes  or  renal  changes  or  both. 

Finally,  because  of  the  similarity  in  origin  of  indol  and  tyro- 
sin, we  ran  parallel  series,  each  with  its  control. 

We  have  no  definite  knowledge  of  the  manner  of  action  or  of 
the  effects  of  tyrosin  in  the  organism.  We  know  but  little  more 
concerning  indol.  We  are  led  to  think  that  massive  doses  of  the 
latter  may  be  consumed  with  no,  or  but  little,  ill  effects  in  normal 
man  (Nesbitt).  Such  effects  are  headache,  insomnia,  confusion 
and  irritability  (Hertet*),  and,  with  decreased  activity  in  the  cells 
in  disposing  of  such  substances,  intoxications  are  possible  (Rich- 
ards and  Rowland).  It  is,  however,  possible  that  comparatively 
small  doses  given  over  long  periods  of  time  may,  even  without 
producing  symptoms,  cause  changes  in  the  organs  which  may 
lead  to  very  serious  results. 

Our  series  of  experiments  deals  with  the  possibilities  of  such 
results. 

In  performing  these  experiments  we  used  rabbits  and  white 
rats.  Originally  we  used  intravenous  injections.  We  used  satu- 
rated aqueous  solutions  of  Kahlbaum's  indol  and  tyrosin. 

For  the  sake  of  brevity  we  shall  at  this  time  merely  summar- 
ize our  results  by  saying  that  after  these  injections  we  have  found 
the  medullas  of  the  adrenals  hyperplastic  and  apparently  hyper- 
trophic, and  that  the  evidences  of  chromafiin  activity  increased  in 
proportion  to  the  number  of  injections.  The  chrome  reaction 
is  similarly  increased.  We  also  found  very  slight  interstitial 
changes  in  the  kidneys. 

We  had  at  the  commencement  of  our  experiments  a  suspected 
relation  between  tyrosin  and  adrenal  changes;  a  suspicion  of  a 
possible  relation  between  indol  and  renal  changes,  and  the  possi- 
bility of  a  relation  between  adrenal  and  renal  changes. 


W  O  O  L  L  E  Y   AND    N  E  W  B  U  R  G  H  121 

From  our  incomplete  results,  the  small  importance  of  which 
we  realize,  we  are  not  justified  in  drawing  any  conclusion,  but  we 
might  suggest  for  the  sake  of  perspective  that,  provided  it  be  true 
that  a  true  hyperactivity  of  the  chromaffin  is  produced  by  one  or 
other,  or  both  of  the  substances  we  have  used,  or  by  other  sub- 
stances of  the  same  chemical  order,  that  is  to  say,  belonging  to 
the  aromatic  series,  it  might  be  suspected  that  such  an  hyperac- 
tivity, extending  over  a  considerable  period  of  time,  may  be  a 
cause,  perhaps  the  cause,  of  the  symptom-complex  known  as  dia- 
betes. This  would  result  from  a  change  in  the  chromaffin-pan- 
creas  equilibrium. 

Eppinger,  to  whom  the  idea  was  possibly  suggested  by  Boinet, 
has  remarked  that  tuberculin  may  be  a  substance  which  of  itself 
produced  inactivity  of  the  chromaffin  tissues  of  the  body,  and  that 
by  means  of  tuberculin  the  pancreas-adrenal  equilibrium  can  be 
upset  on  the  adrenal  side,  that  is  to  say,  in  the  Addisonian  direc- 
tion. In  other  words,  under  the  influence  of  tuberculin  the  glyco- 
lytic function  of  the  organism  is  increased. 

Our  experiments  in  this  direction  have  led  us  already  to  a  tem- 
porary belief,  at  least,  in  Eppinger's  conception.  We  have  found 
that  seven  injections,  each  of  0.5  mg.  of  tuberculin,  led  to  an  in- 
crease of  sugar  consumption  in  rabbits.  A  normal  rabbit  after 
50  gm.  of  glucose  (by  mouth)  showed  0.43  gm.  of  glucose  in  the 
urine  (1.72  per  cent.).  The  same  rabbit  after  seven  injections  of 
tuberculin  showed  0.07  gm.  (0.35  per  cent.).  These  results  with 
tuberculin,  especially  in  view  of  the  fact  that  the  medulla  of  the 
glands  shows  atrophy  after  tuberculin  treatment,  are  interesting 
if  considered  with  the  fact  that  in  the  diagnosis  of  Addison's  dis- 
ease tuberculin  should  be  used  with  the  greatest  circumspection. 
Our  final  suggestion  is  that  it  seems  possible  that  tuberculin  in- 
jection may  be  of  value  in  the  treatment  of  diabetes,  because  of 
its  influence  on  the  chromaffin,  and,  through  that  influence,  be- 
cause of  its  tendency  to  bring  back — to  correct — the  adrenal-pan- 
creas equilibrium.  We  are  continuing  our  work  by  carrying  out 
a  careful  series  of  physiologic  experiments. 


AMYLOID  DEGENERATION  LOCALIZED 
IN  THE  ADRENAL. 


15 Y  PAUL  G.   WOOLLEY,   M.D. 


It  is,  of  course,  a  generally  well  known  fact  that  the  adrenal  is 
frequently  affected  in  conditions  in  which  the  formation  of  amy- 
loid is  widespread.  There  is,  for  instance,  no  lack  of  cases  in 
which,  with  amyloid  changes  in  the  kidney,  spleen  and  liver,  the 
adrenal  is  also  the  seat  of  amyloid  deposits.  But  there  are  few 
cases  in  which  the  adrenal  alone  is  affected,  and  as  far  as  I  know 
there  is  no  description  in  the  literature  of  the  structure  of  the 
amyloid  areas  of  the  adrenal,  with  reference  to  the  finer  effects 
that  are  produced  upon  the  functional  cells  of  that  organ. 

It  is  because  of  the  focalization  of  amyloid  in  the  adrenal, 
and  because  of  the  relation  of  the  changes  in  the  parenchymatous 
cells  of  the  adrenal  cortex  in  the  lesions,  that  I  wish  to  report  the 
following  case : 

Case  No.  158697. — The  patient  was  a  man  of  forty-one  years. 
His  family  history  was  negative.  He  denied  venereals,  but  had 
been  a  heavy  drinker.  He  came  to  the  Cincinnati  Hospital  com- 
plaining of  swelling  of  the  legs  and  abdomen  and  shortness  of 
breath.  He  said  that  he  had  had  "heart  trouble"  for  years,  and 
that  this  became  worse  some  two  months  before  admission.  At 
that  time  he  suffered  with  shortness  of  breath  and  dizziness,  and 
his  ankles  and  feet  began  to  swell.  He  had  pain  in  the  cardiac 
region. 

At  the  time  of  admission  his  lips,  ears  and  nose  were  cyan- 
otic. His  temperature  was  97°  P.,  his  pulse  88  and  his  respira- 
tion 32. 

With  the  exception  of  a  slight  bulging  of  the  upper  left  side 
of  the  sternum,  the  conformation  of  the  thorax  was  normal.  Per- 
cussion showed  a  somewhat  diminished  resonance  over  the  upper 
lobe  and  an  area  of  flatness  over  the  upper  left  sternal  region. 
This  area  was  in  communication  with  the  area  of  cardiac  dullness, 
which  was  increased  downward  and  to  the  left.  Posteriorly  there 
was  also  an  area  of  dulness  6-7  cm.  in  diameter  in  the  region  of 
the  sixth,  seventh  and  eighth  dorsal  vertebras.  Over  this  area 
there  was  distinct  bronchial  breathing. 

A  blowing  systolic  bruit  was  heard  at  the  apex  of  the  heart 

123 


124  DANDRIDGE    MEMORIAL 

and  over  the  tricuspid  area.  A  diastolic  murmur  was  also  present 
at  the  apex.  Over  the  pulmonic  area  there  was  a  distinct  whir- 
ring sound.  The  systolic  bruit  was  transmitted  to  the  axilla  and 
back.  The  abdomen  was  enlarged  and  contained  a  considerable 
amount  of  fluid. 

Three  days  after  admission  the  patient  died  suddenly.  Death 
was  preceded  by  an  increase  of  dyspnea. 

Clinical  Diagnosis. — Myocardial  insufficiency ;  valvular  heart 
lesion;  aneurism  of  the  arch  of  the  aorta;  nephritis;  general  ana- 
sarca. 

Post-mortem  v/as  made  two  hours  after  death. 

The  body  was  that  of  a  fairly  well  developed,  fairly  well  nour- 
ished white  man,  apparently  thirty-five  years  of  age.  Rigor  mor- 
tis was  not  present.  There  was  no  post-m.ortem  lividity.  Scat- 
tered over  the  legs  and  over  the  outer  portions  of  the  arms  were 
numerous  small  white  scars,  averaging  about  3  mm.  in  diameter. 
They  were  slightly  raised  above  the  surface  of  the  skin  and  their 
centers  were  slightly  depressed.  They  were  not  pigmented.  At 
the  base  of  the  glans  penis,  on  the  left  side,  was  a  small  bluish 
area  measuring  about  1  cm.  in  diameter.  There  was  a  general 
edema  of  the  subcutaneous  tissues. 

On  opening  the  chest  cavity,  the  lungs  were  partially  con- 
tracted and  did  not  meet  in  the  median  line.  There  were  numer- 
ous old  fibroid  pleural  adhesions  on  all  sides.  The  lungs  were  of 
a  dirty  gray  color,  and  evidently  contained  an  increased  amount 
of  fibrous  tissue.  At  the  base  of  the  right  lung  was  an  area,  about 
3  cm.  in  diameter,  which  was  harder  and  firmer  than  the  sur- 
rounding tissue.  The  center  of  this  mass  was  soft  and  filled  with 
yellowish  pus.  In  the  left  lung,  about  a  hand's  breadth  (9  cm.) 
from  the  apex,  was  a  small  area  measuring  2  cm.  in  diameter. 
On  section  this  area  was  of  a  yellowish-white  color  and  somewhat 
cheesy  and  gritty  in  consistency.  The  lobes  of  the  lungs  were 
bound  together  by  old  adhesions.  The  right  lung  weighed  425 
gms.,  the  left  250  gms. 

The  pericardium  contained  75  cc.  of  a  clear  straw-colored 
fluid.  The  heart  was  generally  enlarged,  and  the  right  side  was 
markedly  dilated.  The  muscle  tissue  was  pale.  The  anterior 
leaflet  of  the  aortic  valve  was  adherent  to  the  middle  leaflet.  Oth- 
erwise the  valves  appeared  to  be  normal.  In  the  aorta,  just  be- 
yond the  aortic  valve,  were  a  few  small  white  or  milky  patches. 
The  aorta  was  much  smaller  in  diameter  than  normal,  but  other- 
wise showed  no  abnormalities.     The  heart  weighed  425  gms. 

The  peritoneal  cavity  contained  a  large  amount  of  fluid  simi- 
lai  to  that  in  the  pericardium.  The  abdominal  organs  occupied 
their  normal  positions.  The  liver  was  small  and  of  a  reddish- 
brov/n  color.     The  surface  was  very  rough,  and  the  capsule  was 


WOOLLEY  125 

somewhat  thickened  and  in  places  of  a  hyaline  appearance.  The 
gall-bladder  contained  a  greenish-brown  bile.  Its  walls  were 
thickened,  fibrotic,  and  had  a  yellowish-red  mottled  'appearance. 
The  liver  weighed  1,450  gms. 

The  spleen  weighed  130  gms.  It  was  of  a  dark  red  color,  and 
cut  with  slightly  increased  resistance.  Over  the  lower  portion  of 
the  spleen  the  capsule  averaged  5  mm.  in  thickness,  and  was 
white,  firm  and  fibrous.  At  the  lower  pole  of  the  spleen,  under 
this  thin  sclerotic  capsule  and  extending  into  the  substance  of 
the  spleen,  was  a  nodule  similar  in  size  and  appearance  to  the 
one  in  the  apex  of  the  left  lung. 

The  kidneys  each  weighed  130  gms.  On  section  they  were 
somewhat  congested,  cloudy  and  distinctly  edematous.  The  cor- 
tex was  of  normal  thickness.  The  line  of  demarkation  between 
cortex  and  medulla  was  distinct.  The  adrenals  measured  2xlx^ 
inch.  The  medullas  were  congested  and  apparently  hyperplastic. 
The  cortex  showed  no  distinct  evidence  of  abnormality. 

At  the  time  of  necropsy  there  were  no  appearances  that  sug- 
gested amyloid.  Later,  when  sections  of  the  organs  were  studied, 
there  was  no  indication  of  amyloid  in  any  of  the  organs  except 
the  adrenal. 

In  a  few  sections  of  the  adrenal,  a  small  clear  cortical  area, 
measuring  less  than  a  millimeter  in  diameter,  was  visible  to  the 
unaided  eye,  lying  just  outside  the  line  of  demarcation  between 
cortex  and  medulla. 

Microscopically,  these  are'ks  were  composed  of  a  homogen- 
eous ground  substance  in  which  a  considerable  number  of  cells 
resembling  those  of  the  adrenal  cortex  were  imbedded.  There 
were  a  number  of  capillary  blood-vessels  separated  from  the  cells 
by  the  homogeneous  matrix. 

This  hyaline  homogeneous  material  reacted  slowly  but  defi- 
nitely to  the  amyloid  reagents,  best,  perhaps,  with  iodine  and  sul- 
phuric acid.  The  imbedded  cells  were  all  more  or  less  filled  with 
large  and  small  yellowish  refractile  granules  similar  to  those  nor- 
mally present  in  the  adrenal  cortex.  In  other  parts  of  the  cortex 
there  were  smaller  amyloid  areas  more  or  less  irregularly  dis- 
tributed and  confined  to  the  immediate  neighborhood  of  the 
smaller  blood-vessels,  and  only  occasionally  involving  the  cell 
columns.  In  but  a  single  place  in  the  medulla  was  there  any  evi- 
dence of  amyloid,  and  that  was  in  the  walls  of  two  blood-vessels. 

The  medulla  of  the  gland  .showed  a  remarkable  degree  of  con- 


126  DAN  BRIDGE    MEMORIAL 

gestion  and  hyperplasia.  In  sections  of  tissue  fixed  in  bichromate- 
formalin  the  medulla  measured  3  to  4  mm.  in  thickness,  the  cor- 
tex 1  to  1.5  mm.  Everywhere  throughout  the  medulla  the  nests 
and  columns,  surrounded  by  dilated  capillaries,  were  made  up  of 
cells  with  dark-brownish,  finely  granular,  pigmented,  abundant 
protoplasm  and  vesicular  nuclei.  The  size  of  the  cells  varied  im- 
mensely. Some  were  small  with  large  nuclei  and  relatively  small 
amounts  of  protoplasm ;  some  were  very  large  with  abundant 
protoplasm.  All  stages  between  these  extremes  were  found.  Still 
other  cells  had  enormous  vesicular  nuclei,  some  oval,  of'casionally 
cres^^entic,  some  round.  Multinuclear  cells  were  infrequent.  Mi- 
totic figures  were  present. 

The  cortical  cells  showed  no  marked  variation  from  normal. 

The  medullary  ganglion  cells  were  well  preserved. 

We  have,  of  course,  no  basis  from  which  to  speculate  in  the 
meaning  found  in  this  adrenal.  We  might  suggest,  however,  that 
in  this  case  the  appearance  of  amyloid  in  the  adrenal  indicated 
the  first  changes  in  the  process  of  the  production  of  a  general 
amyloidosis. 


ACQUIRED  DIVERTICULA  OF  THE  SIGMOID,  WITH  A 
REPORT  OF  SIX  CASES.* 


BY  ARTHUR  D.  DUNN,    M.D.,   AND  PAUL  G.    WOOLLEY,    M.D. 


At  the  twenty-seventh  Congress  of  Surgery,  Graser  demonstrated 
a  stenosis  of  the  sigmoid  due  to  chronic  hyperplastic  inflamma- 
tion, on  which  an  operation  for  cancer  had  been  performed.  He 
believed  the  portal  of  entrance  for  the  infection  to  be  a  number  of 
acquired  diverticula,  some  of  which  were  seen  entering  the  in- 
flammatory mass.  From  Graser's  paper  dates  the  clinical  interest 
in  the  subject,  for  before  that  time  diverticula  had  been  consid- 
ered merely  pathological  curiosities.  They  had  been  described 
by  Morgagni  (1796),  Fleischmann  (1815),  Albers  (1844),  Hab- 
ershon  (1857),  Klebs  (1869),  Loomis  (1872),  Fischer  (1900) 
and  others. 

Acquired  diverticula  are  of  two  varieties,  the  true  and  the 
false.  True  diverticula  are  merely  wide-mouthed  pouches  whose 
walls  contain  all  of  the  layers  of  the  normal  bowel.  They  are 
the  result  of  an  abnormal  tendency  to  haustrum  formation,  and 
seem  to  be  of  anatomical  significance  only.  False  diverticula,  on 
the  contrary,  are  hernia  form  protrusions  of  the  mucous  mem- 
brane through  the  musrularis,  and  are  of  increasing  clinical  and 
pathological  moment. 

Acquired  diverticula  may  occur  throughout  the  entire  intes- 
tinal tract.  They  have  frequently  been  seen  in  the  duodenum 
in  the  vicinity  of  Vater's  papilla.  They  are  common  in  the  colon, 
and  they  cease  abruptly  at  the  first  portion  of  the  rectum.  Oc- 
casionally they  have  been  observed  in  the  appendix,  where  they 
may  be  the  seat  of  a  condition  which  cannot  be  differentiated 
from  appendicitis.  They  vary  in  number  from  several  hundred 
(400,  Hansemann)  to  an  isolated  protrusion.  They  are  generally 
multiple. 

Since  diverticula  of  the  sigmoid  are  much  more  likely  to  give 

*  From  the  Americun  Journal  of  the  Medical  Sciences,  July,  1911. 

127 


128  DANDRIDGE    MEMORIAL 

rise  to  clinical  manifestations,  your  attention  will  be  directed 
toward  them  only. 

Etiology. — Their  origin  is  still  a  mooted  question.  A  predis- 
position to  diverticulum  formation  undoubtedly  exists,  and  accord- 
ing to  Graser  and  Sudsuki  is  common.  On  miicroscopic  examina- 
tion of  the  sigmoid  in  old  subjects,  the  former  found  small  di- 
verticula in  ten  out  of  twenty-eight  cases,  and  the  latter  in  fifteen 
out  of  forty  cases. 

The  following  theories  as  to  cause  have  been  suggested : 

1.  That  the  fenestra  through  which  the  vessels  penetrate  the 
muscularis  form  loci  minoris  resistentice.  The  vessels  are  sur- 
rounded by  loose  connective  tissue,  which  contains  a  variable 
amount  of  fat.  As  the  individual  ages,  the  fat  increases,  the 
connective  tissue  becomes  weaker,  and  the  fenestra  are  increased 
in  size  by  atrophy  of  the  muscularis.  Intermittent  stasis  also 
stretches  and  increases  the  diameter  of  the  fenestra.  During  pe- 
riods of  cessation  of  stasis,  the  caliber  of  the  vessels  diminish,  and 
loose  space  in  the  "vessel  holes"  results.  These  factors  increase 
the  predisposition.  Accumulation  of  feces  and  gas  incident  to 
constipation,  bowel  atony,  and  abnormal  decomposition  act  to  a 
degree  as  determining  factors.  The  vascular  theory  is  accepted 
by  Fischer,  Koch,  Hansemann,  Berner  and  others,  and  is  cor- 
roborated by  four  of  the  cases  which  we  studied  microscopically. 

2.  Bland-Sutton  believes  that  the  appendices  epiploicae  form 
points  of  lessened  resistance  because,  as  he  has  shown,  their  fat 
is  in  immediate  continuity  with  the  subserous  fat  of  the  intestinal 
wall.  It  is  difficult  to  see,  however,  why  continuity  of  fat  should 
predispose  to  diverticula.  The  process  is  that  of  a  penetration  of 
the  muscularis,  and  it  seems  highly  improbable  that  the  weak 
serosa  and  its  subserous  layer  of  fat  could  play  any  part  in  it.  It 
is  more  probable  that  the  fact  that  blood-vessels  penetrate  the 
muscularis  at  this  point  is  the  chief  reason  for  the  common  inci- 
dence of  diverticula  here.  In  some  cases  an  adherent  appendix 
may  cause  the  production  of  traction  diverticula. 

3.  Franke  believes  that  developmental  anomalies  are  at  the 
basis  of  diverticulum  formation.  What  these  developmental  im- 
perfections are  he  leaves  unspecified. 

4.  Beer  and  Telling  consider  weakening  of  the  muscular  coat 


DUNN    AND    WOOLLEY  129 

in  adult  life  as  the  chief  cause  of  diverticula.  They  do  not  state 
why  the  muscular  wall  should  weaken  in  certain  spots  and  not  in 
others.  They  assume  that  the  vessels  may  "direct  the  path"  for 
the  diverticula.  Beer  states:  "The  fact  that  diverticula  occur 
in  old  people,  in  people  whose  intestines  have  been  more  or  less 
worked  out,  as  evidenced  by  constipation,  points  to  a  muscular 
deficiency,  and  in  this  muscular  weakness  the  cause  of  false  diver- 
ticula must  be  sought." 

5.  Age  seems  to  be  to  some  extent  a  determining  factor.  In 
eighty  cases  the  average  age  was  sixty  years  (Telling).  Forty- 
seven  of  the  eighty  cases  gave  rise  to  clinical  symptoms  at  the 
average  of  fifty-five  years.  The  ages  of  our  six  cases  were  as 
follows :  Without  symplioms,  sevenity-five,  seventy-eight,  and 
unknown;  with  symptoms,  eighty-three  (symptoms  due  to  cicatri- 
cial stenosis  secondary  to  diverticulitis),  forty-five  and  fifty. 

6.  Sex  also  plays  a  part.  Of  eighty-one  cases  fifty-three  were 
male,  twenty-eight  female  (Telling).  Our  six  cases  were  all 
men. 

7 .  Obesity  has  been  emphasized  as  a  causative  factor  by  Klebs, 
Mayo  and  others,  but  it  seems  to  be  only  an  indication  of  invo- 
lution processes  and  thus  only  a  concomitant  of  weakness  in  the 
muscularis  or  in  the  "vessel  holes."  Only  two  of  our  cases 
showed  any  unusual  increase  in  fat, 

8.  Cachexia  and  absence  of  fat  were  marked  in  one  of  our 
cases.  It  might  be  inferred  that  in  individuals  who  had  been 
obese  the  loss  of  fat  would  tend  to  weaken  the  intestinal  wall  by 
leaving  unoccupied  or  loose  spaces, 

9.  The  physiological  role  of  the  sigmoid  must  be  of  some  mo- 
ment in  promoting  diverticulum  formation.  The  feces  are  re- 
tained longest  in  this  segment  (average  ten  to  twenty-four  hours), 
and  its  walls  are  incessantly  subjected  to  changes  in  pressure 
due  to  variations  in  the  quantity  and  quality  of  its  contents,  and 
so  a  predisposition  and  tendency  to  atony  is  inherent  in  the  nor- 
mal function  of  the  sigmoid. 

10.  When  the  physiological  retention  of  feces  becomes  exces- 
sive and  constipation  arises,  the  strain  upon  the  gut  walls  is  abnor- 
mal, and  any  tendency  to  atony  is  aggravated.  Localized  weaken- 
ings are  subjected  to  a  determinative  factor.   The  causal  relation- 


130  DANDRIDGE    M  E  xM  O  R  I  A  L 

sliip  of  constipation  to  diverticulum  fonriation  so  often  observed 
might  seem  to  support  this  view.  Fischer's  doubts  as  to  the  im- 
]>ortance  of  constipation,  however,  are  well  founded.  Its  role  has 
certainly  been  exaggerated,  and  cases  are  numerous  in  which  con- 
stipation has  not  been  recorded.  Only  a  very  small  proportion  of 
the  constipated  have  diverticula.  Abnormal  decomposition  of  re- 
tained contents  with  gas  production  is  probably  of  more  moment. 
Constipation,  if  it  plays  a  part,  must  apparently  be  of  the  atonic 
type  The  writer  knows  of  no  investigation  as  to  this  point.  Any 
factor,  however,  that  will  increase  intrasigmoidal  pressure  must 
influence  the  development  of  diverticula  at  points  of  lessened 
resistance. 

We  may  briefly  summarize  the  etiological  factors,  all  of  which 
may  be  present  to  a  variable  extent  in  every  case,  as  follows:  (1) 
Congenital  or  acquired  anatomical  predispositions  to  localized 
VN^eakness  in  the  wall  of  the  gut.  (2)  The  addition  of  certain 
positive  mechanical  factors  to  the  above  potential  factors,  viz., 
(a)  strain  on  the  bowel  w^all  due  to  the  accumulation  of  gas  and 
feces;  (b)  changes  in  the  caliber  and  structural  strength  of  the 
"vessel  holes"  consequent  on  stasis  and  senile  circulatory  dis- 
turbances, or  on  rapid  loss  of  visceral  fat;  (c)  atony,  v/hich  may 
be  due  to  age,  distention  or  obesity. 

Pathology. — There  is  little  definite  information  on  the  post- 
mortem incidence  of  acquired  diverticula  of  the  sigmoid,  for,  as  a 
rule,  little  attention  is  given  to  this  segment  of  the  gut  in  the 
routine  autopsy,  unless  clinical  manifestations  or  conspicuous 
pathological  alteration  draws  the  attention  thither.  In  seventy- 
eight  cases  in  which  the  sigmoid  was  carefully  examined  by  us  at 
the  autopsy,  acquired  diverticula  were  found  five  times.  Two  of 
the  above  cases  were  clinical.  In  one,  the  diagnosis  was  sus- 
pected almost  to  a  certainty,  in  the  second  it  was  a  "find."  The 
remaining  cases  were  discovered  because  they  were  looked  for. 
False  diverticula  are  usually  situated  near  the  mesenteric  at- 
tachment. According  to  Bland-Sutton,  Franke,  and  Telling,  they 
are  most  commonly  formed  at  the  appendices  epiploicje.  In  three 
of  our  autopsies  they  were  located  at  these  points.  In  one  case 
their  location  was  at  the  mesenteric  attachment.  In  one  case  the 
diverticula  were  located  in  the  vicinity  of  the  appendices,  but 


DUNN    AND    WOOL  LEY  131 

their  relationship  to  them  could  not  be  determined  on  account 
of  the  hyperplasia  of  the  gut  wall  and  an  inflammatory  infiltra- 
tion of  the  immense  amount  of  fat  surrounding  the  sigmoid. 
One  peculiarity  in  this  case  not  hitherto  noted  is  the  location  of 
the  diverticula  on  the  summits  of  the  rugae,  where  they  were  dis- 
covered as  minute  depressions  only  after  careful  search.  One  of 
these  innocent-looking  depressions  led  into  a  fistulous  tract.  Lo- 
cation opposite  the  mesenteric  attachment  has  been  described  by 
Hansemann. 

The  sice  of  acquired  diverticula  varies  from  minute  hernia- 
form  protrusions  of  the  mucosa,  discoverable  only  with  the  micro- 
scope, to  processes  the  size  of  peas  or  grapes.  (Size  of  an  apple 
— Edel;  of  an  egg — Virchow).  They  are  conical,  saccular,  spheri- 
cal, or  teat-like  processes. 

The  ostia  vary  markedly  in  size.  Sometimes  the  diameter  of 
the  opening  equals  that  of  the  average  diameter  of  the  diverti- 
culum. Often  the  openings  are  narrow,  and  although  one  easily 
discovers  the  pouch  on  the  outer  surface  of  the  bowel,  the  mu- 
cosa must  be  scanned  carefully  to  find  the  mouth.  Alany  of  them 
are  distinctly  flask-shaped,  and  their  necks  seem  to  be  constricted 
by  the  penetrated  musculature.  This  shape  is  especially  charac- 
teristic of  diverticula  into  the  appendices  epiploicse,  and  creates 
an  excellent  mechanism  to  prevent  drainage.  Catarrhal  inflam- 
mation may  easily  cause  edema  and  swelling  of  the  mucosa,  and 
thus  completely  occlude  the  neck.  Thus,  there  is  formed  a  thin- 
walled  sac  filled  with  infectious  material  lying  outside  of  the 
gut.  The  peritoneal  cavity  is  protected  only  by  a  thin  membrane 
consisting  of  mucosa,  serosa,  and  possibly  a  few  attenuated  muscle 
fibers.  The  mucosa  itself  is  often  eroded  or  atrophic.  It  may  be 
completely  denuded.    Localized  foci  of  infection  are  common. 

The  coats  of  the  diverticulum  vary.  ^Mucosa,  sub-mucosa  and 
serosa  are  constant.  The  amount  of  muscularis  varies  in  different 
diverticula,  and  in  different  parts  of  the  same  diverticulum.  The 
walls  are  thinnest  at  the  tips  of  the  processes. 

Here  there  may  be  nothing  but  a  thinned  outer  layer  of  mu- 
cosa and  serosa.  In  our  sections  the  penetration  of  the  mus- 
cularis is  clear,  even  though  the  diverticulum  carries  some  mus- 
cle fiber  with  it.     The  contrast  in  the  thickness  of  the  muscular 


132  DANDRIDGE    MEMORIAL 

coating  of  the  diverticulum,  and  of  the  layers  through  which  it 
passes,  is  most  marked.  This  accumulated  musculature  at  the 
neck  is  suggestive  of  a  sphincter.  Beer  and  others  have  sug- 
gested that  the  origin  of  this  picture  is  a  localized  weakening 
of  the  muscularis,  but  this  still  leaves  an  explanation  to  be  ex- 
plained. The  potentiality  for  mischief  which  lies  in  these  struc- 
tures is  evident  from  an  inspection  of  the  section  shown  with  the 
description  of  our  cases. 

The  morbidity  from  false  diverticula  depends  on  the  follow- 
ing factors : 

1.  Thinning  of  the  coats. 

2.  Ulcerative  and  perforative  action  of  retained  concretions 
and  feces. 

3.  Presence  of  pathogenic  micro-organisms. 

4.  Defective  drainage  due  to  (a)  lack  of  an  effective  muscular 
coat;  (b)  closure  of  the  neck  by  edema  of  the  mucosa  second- 
ary to  colitis  or  stasis.  A  mild  catarrhal  colitis  may  occlude  the 
openings,  and  thus  result  in  the  formation  of  a  pocket  of  infec- 
tious material,  from  which  the  peritoneal  cavity  is  poorly  pro- 
tected by  a  coat  of  variable  thinness;  (c)  strangulation  of  the 
opening  by  kinking,  torsion  or  muscular  (sphincter)  action. 

The  following  morbid  processes,  due  to  acquired  diverticula 
of  the  sigmoid  have  been  noted : 

1.  Local  Peritonitis. — Cases  have  been  reported  in  consider- 
able number.  Abscesses  in  the  left  iliac  fossa  have  frequently 
been  drained  and  attributed  to  various  causes,  such  as  left-sided 
appendicitis,  infected  appendices  epiploicae,  colonic  ulceration,  etc. 
This  is  probably  the  most  frequently  observed  clinical  manifes- 
tation of  diverticulitis.  (Telling  collected  twenty-four  cases.) 
One  of  our  cases  was  of  this  type. 

2.  Acute  General  {Diffuse)  Peritonitis. — (a)  With  perfora- 
tion, fourteen  cases  (Telling)  ;  {b)  without  perforation.  Loomis 
(1872)  reports  a  single  case  of  general  peritonitis  in  which  di- 
verticula were  present  in  large  numbers.  He  assumed  that  the 
infection  traversed  the  thin  wall  of  a  diverticulum  without  rup- 
ture. 

3.  Chronic  Hyperplastic  Sigmoiditis. — Within  the  last  few 
years  a  number  of  cases  have  been  reported,  characterized  by  a 


DUNN    AND    WOOLLEY  133 

productive  inflammation  of  the  sigmoid,  which  manifests  itself 
by  disturbed  function  of  the  lower  bowel ;  pain,  intermittent  and 
colicky  in  character;  tenderness  and  constipation,  often  spastic  in 
type  and  frequently  alternating  with  diarrhea.  Mucus  and  occa- 
sionally a  trace  of  blood  are  present  in  the  stools.  Examination 
showed  tenderness  in  the  left  iliac  fossa  with  a  movable  sausage- 
shaped  tumor.  Recent  observations  prove  a  large  percentage  of 
these  cases  to  be  the  result  of  diverticulitis  and  peridiverticulitis. 
Patel  says :  "Peute-etre  un  jour  sera-t-on  droit  de  dire  que  dans 
presque  tons  ces  cas  decrites  sous  le  nom  de  sigmoiditis,  il  s'agit 
de  veritables  diverticulites,  absolument  comme  I'appendicite  a  ete 
substitute  peu  a  pen  a  la  typhlite."  There  is  little  question  but 
that  many  of  the  successful  resections  of  the  sigmoid  for  carci- 
noma have  been  cases  of  infiltrating  sigmoiditis.  A  review  of 
museum  specimens  (Mayo,  Wilson,  Telling,  etc),  is  already  put- 
ting certain  excised  cancers  of  the  sigmoid  into  this  class.  Such 
reports  will  increase  in  frequency  as  the  condition  becomes  bet- 
ter known. 

4.  Cancer. — Four  cases  are  reported  by  Hochenegg,  Stierlin, 
Telling  and  Wilson,  in  which  cancer  has  developed  on  the  basis 
of  a  sigmoiditis  and  perisigmoiditis  secondarj^  to  chronic  diver- 
ticulitis. The  low  grade  of  prolonged  inflammatory  irritation 
which  so  often  precedes  carcinoma  elsewhere  is  here  produced 
by  a  chronic  diverticulitis. 

5.  Stenoses. — These  are  the  result  of  inflammation  in  the  in- 
testinal wall.  Usually  they  are  caused  by  a  productive  inflamma- 
tion, i.e.,  sigmoiditis  and  perisigmoiditis,  which  narrows  the  lu- 
men of  the  gut.  The  mucosa  is  thrown  into  folds,  but,  as  a  rule,  is 
not  ulcerated.  Cicatricial  contraction  following  a  diverticulitis 
may  produce  stenosis,  as  is  clearly  shown  by  one  of  our  speci- 
mens.    Telling  reports  the  only  other  case  in  tHe  literature. 

6.  Adhesions. — Adhesions  produce  symptoms  by :  (a) Traction 
and  constriction.  The  obstruction  is  commonly  due  to  the  fact 
that  the  small  bowel  becomes  adherent  to  the  inflammatory  area; 
(b)  adhesions  of  the  gut  to  the  bladder,  with  vesicosigmoidal 
fistula.  Telling  found  adhesions  reported  sixteen  times  and  fistula 
eleven  times. 

7.  Chronic  Mesenteritis. — Riedel,  Brehms,  Ries,  Simpson  and 


134  DANDRIDGE    MEMORIAL 

Gardinier  have  called  attention  to  the  probable  importance  of  sig- 
moid mesentery,  a  state  which  predisposes  to  volvulus.  One  of 
our  cases  was  of  this  type. 

8.  Metastatic  Suppuration. — Whyte  (1906)  has  reported  the 
only  case  of  this  type.  A  limited  necropsy  disclosed  multiple 
abscesses  of  the  liver.  The  original  focus  was  supposed  to  be 
an  inflamed  diverticulum  of  the  sigmoid  containing  a  fecal  con- 
cretion. 

9.  Perforation  Into  a  Hernial  Sac. — Stierlin  has  reported  a 
case  of  suppuration  into  a  hernial  sac  from  a  perforated  diver- 
ticulum in  an  incarcerated  sigmoid. 

Case  I. — B.  K.,  male,  aged  forty-live  years.  The  family  his- 
tory is  negative,  and  the  personal  history  also  until  one  and  one- 
half  years  before  the  present  illness,  when  the  patient  had  an 
attack  of  pain  and  distress  in  the  hypogastrium  with  temperature. 
There  was  some  diarrhea  and  tenesmus.  Constipation  was  not 
present  at  any  time.  lie  went  to  bed  for  several  days  on  a  re- 
stricted diet  and  recovered  rapidly. 

Except  a  few  fleeting  pains  and  an  occasional  sense  of  ftill- 
ness  in  the  lower  quadrants,  which  disappeared  wuth  catharsis, 
nothing  of  moment  occurred  for  one  and  one-half  years,  when, 
after  a  few  days  of  indefinite  distress  in  the  hypogastrium,  he 
suffered  severe  pains  in  the  lower  abdomen,  which  were  accom- 
panied by  dizziness,  faintness,  chill,  temperature  of  103°,  and 
later  sweating.  The  bowels  had  been  free,  but  with  some  griping 
and  soreness.  The  patient  went  to  bed  on  a  restricted  diet,  and 
for  several  days  had  an  irregular  temperature,  ranging  from  99° 
to  103.5°,  accompanied  by  distress  in  the  lower  abdomen.  Exami- 
nation brought  out  the   following   facts : 

The  patient  was  a  well-developed,  middle-aged  man.  His  com- 
plexion was  muddy,  his  tongue  coated,  and  his  breath  foul.  Ex- 
aminations of  the  heart,  nervous  system,  and  lungs  were  negative 
except  for  the  rapidity  of  heart  and  for  signs  of  retraction  at 
the  left  apex.  The  abdomen  was  uniformly  distended  and  tym- 
panitic. There  was  diffuse  tenderness  below  the  umbilicus,  which 
was  best  defined  in  the  left  iliac  fossa,  and  in  the  median  line, 
where  he  always  referred  his  pain.  No  tumor  mass  could  be  dem- 
onstrated.   A  slight  visceromotor  reflex  was  present  in  both  lower 


D  U  N  N    A  N  D    W  O  O  L  L  E  V  135 

quadrants,  but  was  most  marked  on  the  left.  There  was  no 
area  of  cutaneous  hyperesthesia.  Neither  testicle  was  tender. 
Rectal  examination  was  negative.  The  leukocyte  count  was  15,- 
000.  The  urine  contained  much  indican,  but  was  otherwise  nega- 
tive. The  stools  were  very  offensive,  contained  a  little  mucus, 
but  neither  blood  nor  pus.  Large,  thick  Gram-positive  bacilli 
were  present  in  large  numbers.  The  pulse  was  rapid  ( 100  to 
130). 

With  colonic  irrigation  and  on  a  diet  of  buttermilk  and  car- 
bohydrates the  patient  slowly  improved.  For  a  month  there 
were  occasional  attacks  of  pain,  with  a  little  temperature,  which 
were  relieved  by  flushings.  Convalescence  was  slow.  Several 
leukocyte  counts  during  this  period  gave  an  average  of  8,000  to 
10,000.  Indican  was  more  or  less  constantly  present  until  con- 
valescence w-as  well  established.  A  diagnosis  of  intestinal  toxemia 
with  possible  sigmoiditis  was  made  at  that  time. 

The  patient  left  home  and  did  fairly  well  for  one  month,  when 
he  was  taken  with  sudden,  severe  pain  in  the  hypogastrium,  hur- 
ried to  the  hospital,  and  was  operated  upon  with  the  diagnosis 
of  appendicitis.  In  a  personal  communication  the  surgeon  stated 
that  *'the  appendix  was  thickened  and  slightly  injected,  but  I  must 
confess  it  hardly  seemed  sufficiently  involved  to  account  for  the 
large  amount  of  turbid  fluid  which  we  found  in  the  lower  abdo- 
men. There  were  no  adhesions  about  the  cecum,  which  was 
apparently  normal.     I  did  not  examine  the  sigmoid  colon." 

One  month  later  the  patient  returned  for  treatment.  His 
distress  had  returned  after  the  operation,  although  not  to  the 
same  degree.  A  strict  dietetic  and  hygienic  regime,  with  colonic 
flushing  gradually  brought  the  patient  into  the  best  health  he  had 
enjoyed  for  several  years.  Strict  injunctions  against  excessive 
indulgence  in  proteids,  especially  high  meats  and  cheese,  were 
given,  as  experience  had  proved  that  a  minimum  of  proteid  was 
accompanied  with  less  distress.  With  much  proteid  ingestion,  in- 
dican always  appeared  in  the  urine  and  undigested  meat  fibers 
in  the  stools.  When  the  diet  was  strictly  followed,  the  stools  lost 
their  offensiveness,  the  gas  diminished,  and  the  number  of  Gram- 
positive  bacilli  decreased.  Repeated  rectal  examinations  were 
negative. 


136  DANDRIDGE    MEMORIAL 

After  three  months  of  comparative  freedom  from  trouble, 
the  patient  committed  two  dietetic  indiscretions  within  twenty- 
four  hours.  Pain  and  distress  in  the  hypogastrium  followed 
with  temperature  ranging  from  99°  to  104°,  and  a  pulse  of  100 
to  120.  His  condition  improved  slowly  for  five  days  under  treat- 
ment, when  a  sudden,  sharp  pain  followed  an  injection  of  water. 
The  pain  was  so  severe  that  morphine  was  given  before  the  pa- 
tient was  seen.  On  examination  there  was  considerable  tender- 
ness in  the  lower  abdomen,  some  rigidity,  but  no  cutaneous  hy- 
peresthesia. Rectal  examination  was  negative.  There  was  a  lit- 
tle nausea,  but  no  vomiting.  A  tumor  mass  could  not  be  demon- 
strated at  this  time ;  there  was  some  pain  at  the  end  of  urination. 
On  several  occasions  during  the  next  few  days  the  stools  showed 
a  little  pus,  mucus  and  blood.  Ten  days  later  a  mass  had  clearly 
defined  itself  in  both  iliac  fossa,  and  could  be  detected  per  rectum 
as  an  irregular,  elastic,  bulging  body.  The  patient's  general  ap- 
pearance was  decidedly  septic,  and  he  was  removed  to  the  hos- 
pital for  operation.     Leucocytes,  40,000. 

From  the  clinical  course  it  was  assumed  that  the  condition 
was  a  localized  purulent  peritonitis  rising  from  the  sigmoid.  A 
chronic  ulcerative  process  was  excluded  on  account  of  the  absence 
of  blood  and  pus  in  the  stools  until  the  last  few  days.  Perfora- 
tion of  a  carcinoma  was  unlikely  from  the  length  of  the  clinical 
course  (two  years),  the  absence  of  signs  of  stenosis,  the  almost 
entire  absence  of  blood,  the  absence  of  a  tumor  until  a  few  days 
previous,  the  character  of  the  tumor  and  its  rapid  development. 
By  exclusion,  diverticulitis  of  the  sigmoid  with  perforation  of  an 
infected  diverticulum  resulting  in  a  pelvic  abscess  was  considered 
probable. 

Operation. — An  incision  was  made  in  the  median  line,  and  in- 
asmuch as  the  most  prominent  part  of  the  tumor  mass  seemed  to 
the  surgeon  to  be  on  the  right  side,  a  wide  incision  was  made  well 
to  the  right  of  the  rectus  muscle,  and  free  drainage  instituted. 
The  case  passed  from  observation,  and  death  took  place  about  six 
weeks  after  the  operation.    The  autopsy  report  was  as  follows: 

Operation  about  ten  hours  after  death.  Skin  very  pale.  Slight 
rigor  mortis.  Peripheral  lymph  glands  not  enlarged.  Two  oper- 
ative wounds  on  abdomen — one  in  mid-line  about  10  cm.  long. 


DUNN    AND    woo  LLEY  137 

one  over  appendix  about  7.5  cm.  long.  The  latter  drained.  Sub- 
cutaneous fat  well  developed. 

Upon  opening  the  peritoneal  cavity  it  was  seen  that  the  omen- 
tum was  adherent  over  the  whole  anterior  surface  of  the  perito- 
neum, and  less  extensively  to  the  intestinal  coils.  It  was  rolled 
into  a  mass  in  the  left  hypochondrium. 

The  intestinal  coils  were  more  or  less  generally  adherent  by 
old  fibrous  adhesions,  and  were  also  adherent  to  the  parietal 
peritoneum  in  the  right  flank.  The  coils  of  the  ileum  were  closely 
adherent  to  one  another,  and  the  lower  ones  were  also  adherent  to 
the  sigmoid  by  old  and  recent  adhesions. 

The  cecum  was  bound  down  by  adhesions,  most  of  them  recent, 
the  results  of  an  operation  done  some  days  before  to  drain  the 
cecal  and  pelvic  regions.  There  was  no  pus  in  the  pelvis  or  about 
the  cecum.     The  appendix  had  been  removed. 

The  intestines  were  -^are  fully  dissected  out,  and  no  other  pro- 
cess than  an  adhesive  fibrosis  was  encountered  until  the  lower 
loops  of  the  small  intestines  were  dissected  away  from  the  sig- 
moid, just  at  the  brim  of  the  pelvis.  At  this  point  an  abscess 
cavity  situated  under  the  sigmoid  and  walled  ofT  by  the  small  in- 
testine was  opened. 

As  the  large  intestine  was  removed,  pus  was  again  encountered 
to  the  left  and  beneath  the  descending  colon  and  sigmoid.  This 
suppurative  process  could  be  traced  to  the  abscess  cavity  men- 
tioned above  and  to  a  larger  one  to  the  left  of  it,  in  the  postin- 
testinal  tissues,  and  just  at  the  brim  of  the  pelvis.  The  process 
had  apparently  also  extended  down  (judging  from  the  adhesions), 
but  this  extension  had  been  limited  by  adhesions  in  the  pelvis. 
Extending  up  along  and  behind  the  descending  colon,  the  line 
of  extension  of  suppuration  could  be  followed  to  the  spleen, 
which  was  half  enclosed  in  an  abscess  cavity. 

An  incision  through  the  diaphragm  from  below  and  explora- 
tion of  the  left  pleural  cavity  occasioned  a  gush  of  foul-smelling, 
greenish-yellow,  thin  ous,  to  the  amount  of  about  500  c.c. 

The  thorax  was  then  opened  and  examined.  The  left  lung  was 
partially  compressed  by  an  empyema  that  extended  from  the  dia- 
phragm to  near  the  apex.  The  pleura  was  covered  by  a  green- 
ish-yellow fibrinopurulent  exudate.  The  left  apex  was  th.e  seat  of 
a  large  healed  scar,  and  scattered  about  on  the  pleura  and  in  the 
pulmonary  tissue  were  fibroid  and  calcareous  obsolescent  tuber- 
cles. 

The  right  lung  was  also  the  seat  of  a  healed  tuberculous  pro- 
cess, the  pleura  being  thickly  studded  with  obsolescent  tubercles, 
especially  at  the  junction,  posteriorly,  of  the  interlobar  clefts. 

The  heart  was  pale,  but  otherwise  normal. 

The  liver  was  sm.all,  pale,  and  exceedingly  soft. 


138  DANDRIDGE    MEMORIAL 

The  kidneys  were  very  large  and  pale.  The  capsules  stripped, 
leaving  an  un'torn  surface.  Section  of  the  organ  showed  the  cor- 
tex enlarged,  pale  and  granular  in  appearance,  with  little  line  of 
demarcation  between  it  and  the  medulla. 

The  adrenals  were  normal. 

The  pancreas  was  normal. 

The  spleen  was  of  normal  size,  but  soft,  and  the  seat  of  an 
acute  suppurative  perisplenitis. 

When  the  intestines  were  opened  it  was  seen  that  the  small 
intestine  was  atrophic,  the  walls  thinned,  the  rugse  not  prominent, 
and  the  mucosa  thinned.  P'rom  the  cecum,  down  the  sub-mucosa 
and  the  muscularis  became  gradually  thickened  until,  in  the  vicin- 
ity of  the  brim  of  the  pelvis,  the  wall  was  from  two  to  five  milli- 
meters thick  and  perisigmoidal  and  rectal  tissues  were  generally 
firm  and  infiltrated. 

The  sigmoid  and  rectum  showed  accentuated  diverticular 
pouches,  all  of  which  had  thinned  distal  ends  and  mouths,  about 
which  the  sub-mucosa  and  the  muscularis  were  very  thick  and 
edematous.  Extending  from  the  distal  end  of  one  of  these 
pouches  was  a  sinus,  surrounded  by  thickened  fibroid  walls,  that 
communicated  with  the  larger  postcolonic  abscess  cavity.  From 
this  pouch  or  diverticulum  the  suppurative  process  had  appar- 
ently originated.  The  tops  of  the  folds  of  the  descending  colon 
and  sigmoid  showed  number  of  small  areas  having  somewhat  the 
appearance  of  shallow  ulcers.  These  areas  measured  not  more 
than  one  by  two  millimeters.  They  had  slightly  thickened,  raised 
and  rounded  margins  and  gray  bases. 

Anatomical  Diagnosis. — Anemia;  catarrhal  sigmoiditis  and 
proctitis ;  diverticulum  formation ;  chronic  perforative  diverticu- 
litis; suppurative  perisigmoiditis,  pericolitis  and  perisplenitis;  em- 
pyema ;  parenchymatous  degeneration  of  the  kidneys ;  fatty  re- 
generation of  the  liver;  obsolescent,  calcareous  pulmonary  tuber- 
culosi,s ;  left  apical  scar;  general  organized  peritoneal  adhesions; 
operative  wounds. 

The  striking  clinical  features  of  this  case  are  the  absence  of 
constipation,  the  indefiniteness  of  the  bowel  disturbance,  the  re- 
peated presence  of  large  quantities  of  indican  in  the  urine,  the 
favorable  influence  of  a  proteid  diet,  the  persistent  rapidity  of 
the  pulse  in  all  his  attacks,  the  distress  at  the  end  of  urination,  the 
fact  that  perforation  evidently  followed  distension  of  the  sigmoid 
with  water,  the  fact  that  a  surgeon  of  high  diagnostic  ability 
operated  for  what  seemed  to  be  an  acute  attack  of  appendicitis,  the 
interesting  disitribution  of  the  tumor  mass,  which  extended  from 
the  left  iliac  fossa  dov/n  into  the  cul-de-sac  and  up  into  the  right 


DUNN    A  N  D    WOOL  L  E  Y  139 

iliac  fossa,  where  it  reached  its  greatest  prominence,  and  that  this 
led  a  surgeon  of  large  experience,  after  making  a  median  explo- 
ratory incision,  to  drain  the  apex  of  the  abscess  in  the  right  ihac 
fossa,  with  the  belief  that  the  seat  of  the  trouble  was  there. 

Case  II. — The  following  case  was  seen  with  Dr.  Schleier,  of 
Omaha.  J.  S.,  male,  aged  eighty-three  years.  The  patient  en- 
tered St.  Joseph's  Hospital,  December  9,  1908,  in  a  semicomatose 
condition.  No  history  could  be  obtained  except  that  three  days 
before  admission  he  had  had  some  trouble  in  passing  urine,  and 
had  therefore  been  catheterizcd.  Subsequent  urin'ation  had  been 
free  and  the  urine  bloody. 

General  examination  proved  negative,  except  for  pulmonary 
emphysema  and  a  well-developed  arteriosclerosis.  The  abdomen 
was  distended.  Peristaltic  waves  could  be  seen  starting  in  the 
region  of  the  cecum,  disappearing  in  the  right  hypochondrium, 
and  again  appearing  at  the  median  line,  thence  proceeding  to  the 
left  and  downward  to  the  hypogastrium.  There  was  no  abdom- 
inal rigidity.  There  was  tenderness  posteriorly  over  both  kid- 
neys, with  an  area  of  renal  hyperesthesia  on  both  sides  above  the 
crest  of  the  ilium.  There  was  no  abdominal  tenderness.  The 
bedsheets  were  stained  with  bloody  urine;  a  specimen  could  not 
be  obtained  by  catheterization.     The  breath  was  not  urinous. 

Recta!  Examination. — The  rectum  was  ballooned,  the  pros- 
tate moderately  enlarged,  but  not  tender.  No  tumor  mass  was 
palpable. 

Clinical  Diagnosis. — Chronic  intestinal  obstruction,  probably 
due  to  stricture,  cause  unknown.  Without  a  urine  examination  a 
chronic  intestinal  toxemia  was  suggested  as  a  possible  cause  of 
the  hematuria.  Colotomv  was  advised,  and  performed  by  Dr. 
Schleier.    Death  occurred  about  eighteen  hours  after  operation. 

Autopsy  was  performed  eight  hours  after  death.  The  patient 
was  a  somewhat  emaciated  elderly  man.  There  was  moderate 
edema  and  posterior  congestion  of  both  lungs,  and  marked  senile 
emphysema.  The  heart  was  normal  in  size :  there  was  tremendous 
calcification  of  the  mitral  valves  and  complete  calcification  of 
certain  areas  in  the  coronary  arteries  ;  thei"e  was  also  calcification 
of  the  aortic  valves  and  marked  atheroma  of  the  aorta  through- 
out its  entire  length.  The  celiac  axis  was  almost  completel)^  ob- 
literated. The  large  intestine  was  dilated  throughout  its  entire 
length ;  the  hepatic  flexure  was  adherent  beneath  and  covered  by 
the  liver,  a  condition  which  explains  why  peristalsis  could  not 
be  seen  in  this  region.  A  colotomy  wound  was  observed  at  lower 
part  of  descending  colon.  There  was  a  stricture  at  the  junction 
of  the  middle  and  lower  third  of  the  sigmoid.  Numerous  false  di- 
verticula were  present  in  the  area  of  the  structure,  which  was 


140  DANDRIDGE    MEMORIAL 

about  one  and  one-half  inches  long.  There  was  a  slight  perisig- 
moiditis at  the  site  of  the  stricture.  Diverticula  were  numerous 
for  a  distance  of  a  foot  or  two  above  the  stricture.  They  varied 
in  depth ;  their  mouths  were  generally  wide,  and  they  entered 
the  appendices  epiploicze.  Ihere  was  atrophy  of  the  wads  of  the 
colon  and  of  the  small  intestine.  The  kidneys  were  normal  in 
size,  the  capsules  stripped  easily,  and  the  surface  slightly  gran- 
ular. The  cortex  was  atrophic,  but  there  were  no  gross  signs 
of  inflammation.  The  pelvis  and  both  kidneys  were  markedly 
injected  and  covered  with  a  dirty,  sanguinopurulent  exudate. 
The  ureters  were  distended  and  similarly  inflamed.  They  were 
so  red  and  injected  as  to  look  like  veins  from  the  outside.  The 
bladder  was  thickened  and  markedly  injected.  The  bladder  con- 
tained a  small  amount  of  bloody  urine,  which  showed  pus  cells 
and  desquamated  epithelium  in  large  amounts.  There  were  micro- 
scopic clumps  of  a  dozen  or  more  epithelial  cells  together,  show- 
ing that  desquamation  en  bloc  of  areas  of  bladder,  ureteral  and 
pelvic  epithelium  had  occurred.  The  prostate  was  hypertrophied ; 
there  was  marked  peripheral  arteriosclerosis,  with  extensive  de- 
posits of  lime  salts  in  the  vessel  walls.  The  pathological  diag- 
nosis was  emphysema  and  passive  congestion  of  the  lungs; 
coronary  arteriosclerosis  and  calcareous  deposits  in  mitral  and 
aortic  valves ;  general  arteriosclerosis ;  passive  congestion  of 
liver  and  spleen ;  senile  atrophy  of  spleen ;  chronic  intestinal  ob- 
struction due  to  benign  cicatricial  stenosis  of  sigmoid;  false 
diverticula  of  the  descending  colon  and  sigmoid,  especially  at  area 
of  stricture;  dilation  and  atrophy  of  the  colon;  hypertrophy  of 
the  prostate ;  ascending  cysto-utero-pyelitis. 

The  intimate  relation  of  the  numerous  false  diverticula  to  the 
stenosed  areas  in  this  case  makes  probable  their  pathogenic  sig- 
nificance in  benign  cicatricial  stenosis  of  the  sigmoid. 

Case  III. — S.  B.,  farmer,  aged  fifty  years,  entered  St.  Joseph's 
Hospital,  January  4,  1909.  The  patient  was  in  a  stuporous  con- 
dition, and  the  following  history  was  obtained  with  difficulty: 
The  duration  of  illness  was  indefinite  and  onset  had  been  grad- 
ual. The  patient  complained  of  intermittent  abdominal  pain, 
which  was  described  as  "sore,  colicky,"  of  belching,  headache, 
weakness  and  of  constipation.  His  bowels  had  not  moved  at  all 
for  three  days,  and  not  well  for  several  weeks  previously.  No 
pulmonary,  cardiac  or  renal  symptoms  could  be  elicited.  The  past 
history  was  negative  except  for  indefinite  trouble  with  the  lower 
bowel  and  constipation.  Later,  a  history  was  obtained  of  a  dis- 
turbance, nine  months  previous,  in  the  lower  abdomen,  which 
lasted  several  weeks,  and  was  characterized  by  colicky  pains  and 
distress  in  the  median  line  and  to  the  left,  alternating  diarrhea  and 
constipation  with  mucus  in  the  stools,  fever  and  soreness  in  the 


DUNN    AND   WOOLLEY  141 

left  lower  quadrant.  The  condition  of  the  patient  wlien  first 
seen  was  as  follows:  lie  was  an  emaciated,  medium-sized  man, 
stupid  in  appearance,  and  apparently  of  some  sixty  years  of  age. 
He  lay  quietly  in  bed,  yawned  continuously,  his  eyes  were  half 
closed,  and  he  paid  but  little  attention  to  what  was  going  on 
around  him.  It  was  necessary  to  speak  loudly  and  prod  him  to 
obtain  answers  to  questions.  Both  lids  were  equally  ptotic,  but 
he  could  raise  them  with  the  assistance  of  the  frontal  muscles 
to  the  level  of  the  iris.  The  pupils  were  equally  contracted,  and 
reacted  slightly  to  light  and  distance.  The  breath  was  foul  and 
the  teeth  poor.  Vision  seemed  good.  There  was  no  asymmetry 
in  muscle  power.  The  patient  could  recognize  a  watch  tick  for  a 
distance  of  only  about  an  inch  from  each  ear.  Examination  of 
the  neck,  lungs  and  heart  were  negative.  The  abdomen  was  soft 
and  not  especially  tympanitic.  The  liver  and  spleen  were  nega- 
tive. Peristaltic  waves  occasionally  could  be  seen  traversing 
the  hypogastric  region  from  right  to  left.  They  were  about  two 
to  three  inches  in  breadth,  and  were  accompanied  by  signs  of 
distress  and  rubbing  of  the  abdomen.  Rectal  examination,  save 
for  "ballooning,"  was  negative.  No  tumor  mass  was  palpable. 
The  urine  was  highly  concentrated.  It  contained  indican  and  uro- 
bilinogen (Ehrlich's  aldehyde  reaction)  in  large  amounts,  a  trace 
of  albumin  with  occasional  hvalin  and  granular  casts.  The  su- 
perficial reflexes  were  markedly  diminished,  and  the  deep  re- 
flexes were  faint  or  absent,  but  svmmetrically  so.  The  tempera- 
ture was  101°,  and  the  pulse  70.  An  injection  of  warm  olive  oil 
was  ordered,  with  a  mercurial  and  saline,  which  brought  away  a 
large  amount  of  fecal  material.  The  mental  condition  bright- 
ened for  several  days.  Then  relapses  occurred  at  varving  inter- 
vals vvith  conditions  similar  to  those  described.  The  trouble  al- 
ways could  be  relieved  by  a  rectal  injection  of  one  to  two  quarts 
of  water.  A  diagnosis  of  chronic  intestinal  obstruction,  of  un- 
known cause,  in  the  region  of  the  sigmoid,  was  made  at  this  time. 
On  January  25,  1909,  the  patient  developed  a  double  lobar  pneu- 
monia, which  lasted  ten  days.  During  this  time  injections  of 
water  v.ere  given  each  day. 

On  February  28,  1909,  another  attack  of  pneumonia  occurred 
which  produced  stupor  and  was  accompanied  by  signs  of  intestinal 
obstruction,  e.g.,  peristalsis  and  obstipation,  which  were  relieved 
only  by  repeated  injections  of  both  oil  and  water.  A  large  sacral 
decubitus  four  inches  in  diameter  developed  at  this  time.  Several 
attacks  of  obstruction  followed,  which  were  easily  remedied  by 
injections.  During  intervals  of  from  one  week  to  ten  days  the 
patient  had  normal  although  constipated  stools. 

It  was  clear  that  an  intermittent  intestinal  obstruction  existed. 
This  must  have  been  caused  by  a  mechanical  factor  prevailing 


142  DAN  BRIDGE    MEMORIAL 

only  at  intervals.  The  occasional  copious  and  well-formed  move- 
ments spoke  against  stricture.  The  constant  absence  of  blood  in 
the  stools,  and  of  a  tumor  mass,  spoke  against  malignant  disease. 
There  was  no  evidence  of  hernia.  Of  causes  that  could  produce 
.such  a  frequent  recurrence  of  obstruction,  followed  by  free  in- 
tervals, only  two  could  well  be  assumed.  The  first  was  adhesions. 
But  a  band  could  hardly  produce  this  picture  by  mere  constriction. 
Traction  of  an  adhesion  on  a  loop  of  intestine  might  cause  kinking 
when  influenced  by  changes  in  intra-intestinal  pressure,  and  by 
variations  in  the  position  and  caliber  of  the  gut,  both  of  which 
factors  are,  to  a  certain  extent,  dependent  on  the  intestinal  con- 
tents. The  second  possible  cause  was  intermittent  volvulus  upon 
the  basis  of  cicatrization  and  retraction  of  the  mesosigmoid  form- 
ing an  axis  on  which  rotation  of  the  sigmoid  might  occur.  Such  a 
condition  might  have  accounted  for  an  intermittent  intestinal 
obstruction,  which  Vi^as  not  relieved  by  catharsis,  but  by  rectal 
injections.  A  history  of  intermittent  intestinal  trouble  with  fever, 
pain,  and  diarrhea,  with  the  presence  of  blood  the  year  before, 
suggested  the  possibility  of  such  a  condition. 

Operation  was  advised  on  the  basis  of  a  diagnosis  of  inter- 
mittent chronic  intestinal  obstruction,  due  to  volvulus  or  to 
adhesions.  An  old  inflammatory  process  resulting  from  a  diver- 
ticulitis was  suggested  as  a  possible  causa  morhi. 

The  operation  was  performed  by  Dr.  C.  C.  Allison.  An  in- 
cision was  made  to  the  left  of  the  median  line.  The  upper  and 
lower  segments  of  the  sigmoid  were  found  separated  b)'  about  one 
inch  of  scarred  mesosigmoid.  There  were  slight  adhesions 
running  from  the  origin  of  the  sigmoid  to  the  parietal  peritoneum. 
Several  diverticula  were  seen  close  to  the  mesenteric  attachment 
in  the  vicinity  of  the  retracted  mesosigmoid.  It  could  not  be 
demonstrated  without  opening  the  gut,  that  the  cicatrization  was 
secondary  to  a  diverticulitis,  and  so,  although  the  existence  of  the 
diverticula  may  have  been  a  coincidence,  yet  inference  to  the 
contrary  is  permissible.  The  upper  limb  of  the  sigmoid  was  freed 
from  adhesions  and  stitched  to  the  parietal  peritoneum  higher  up. 
A  complete  recovery  took  place. 

Case  IV. — N.  A.  C,  male,  aged  seventy-five  years.  The  case 
was  a  coroner's  autopsy.  The  anatomical  diagnosis  was:  Myo- 
malacia cordis ;  sclerosis  and  obliteration  of  the  right  coronary 
artery;  general  arteriosclerosis;  passive  congestion  of  liver,  spleen 
and  kidneys;  chronic  interstitial  nephritis;  pulmonary  emphy- 
sema. Several  false  diverticula  of  the  sigmoid  were  found  enter- 
ing the  appendices  epiploicse. 

Case  V. — E.R.,  male,  the  anatomical  diagnosis  was :  Healed 
tuberculosis  of  both  apices;    chronic  bilateral  pleural  adhesions; 


DUNN    AND    WOOLLEY  143 

dilatation  and  hypertrophy  of  the  heart ;  myomalacia  cordis  with 
cardiac  aneurysm ;  passive  congestion  of  lungs,  liver,  kidney,  and 
spleen  ;  cholelithiasis ;  arteriosclerotic  kidney  ;  diverticula  of  the 
sigmoid  and  descending  colon.  The  diverticula  were  located  in 
the  vicinity  of  the  mesenteric  attachment.  Their  walls  were  ex- 
tremely thin,  and  they  contained  inspissated  feces. 

Case  V'I. — The  case  was  a  coroner's  autopsy.  The  subject  was 
an  elderly  obese  male,  of  unknown  age.  The  anatomical  diagnosis 
was :  Edema  of  lower  extremities  ;  passive  congestion  and  edema 
of  the  lungs ;  hypertrophy  and  dilatation  of  the  heart,  especially 
of  the  left  ventricle;  degeneration  of  the  myocardium;  passive 
congestion  of  the  liver,  spleen,  and  kidneys;  chronic  interstitial 
nephritis;  false  diverticula  of  the  sigmoid.  The  sigmoid  was 
surrounded  with  a  large  amount  of  fat,  and  the  appendices 
epiploicae  consisted  of  large  fatty  masses.  Six  false  diverticula 
could  be  seen  penetrating  these  fatty  masses. 

Diagnosis. — It  can  be  easily  seen,  from  the  brief  resume  of  the 
pathology  of  diverticulum  disease,  that  the  symptoms  may  be 
manifold  and  difficult  of  interpretation.  The  diagnosis  is  seldom 
easy,  rarely  certain,  and  often  impossible.  Franke  was  able  to 
collect  from  the  literature  only  two  cases  in  which  the  diagnosis 
had  been  made.  To  these  he  added  a  case  of  his  own.  Graham 
recently  suggested  the  diagnosis  in  one  of  Mayo's  cases.  To 
appreciate  the  possibilities  is  a  long  step  in  the  direction  of  a  diag- 
nosis, which  must  be  made  largely  by  exclusion.  The  most  easily 
recognizable  condition  is  that  of  the  so-called  "left-sided  appendi- 
citis." There  is  pain,  gastric  disturbances,  tenderness,  and  rigidity 
in  the  left  lower  quadrant,  with  temperature  and  leukocytosis; 
abscess  formation  often  appears  later.  Another  class  of  cases 
that  is  moderately  easy  of  recognition  is  that  of  chronic  hyper- 
plastic sigmoiditis.  This  has  been  treated  as  a  disease  entity  by 
Ewald,  Boaz,  Rosenheim,  and  others,  but  it  is  possible  that  diver- 
ticulitis may  be  found  a  basis  for  it.  In  this  complex  there  is 
always  intermittent  pain,  disturbed  function  associated  with  ir- 
regularity of  bowel  action,  gas,  and  often  spastic  stools  in  which 
there  is  frequently  an  increase  in  mucus  and  occasionally  a  trace 
of  blood.  Physical  examination  discloses  a  tender  sausage-shaped 
tumor  which  may  be  either  adherent  or  freely  movable,  and  which 
varies  in  size  from  time  to  time.  Infiltration  may  be  felt  occa- 
sionally per  rectum..     Sigmoidoscopy  shows  a  swollen,  reddened. 


144  DAN  BRIDGE    MEMORIAL 

rugous  mucosa,  and  often  narrowing  of  the  lumen  of  the  gut. 
Obstructive  symptoms  may  be  present,  but  are  not  so  common  as 
in  cancer,  from  which  condition  it  must  be  differentiated.  In 
carcinoma  the  clinical  course  is  more  progressive  and  definite.  Its 
duration  is  limited ;  ulceration  with  blood  in  the  feces  is  the  rule, 
and  when  blood  once  appears  it  is  usually  quite  constant.  The 
tumor  is  harder,  more  likely  to  be  movable,  definitely  circum- 
scribed, constantly  increases  in  size,  and  is  not  elongated.  Bladder 
symptoms  are  apt  to  be  frequent  in  diverticulitis,  as  the  bladder  ir; 
often  involved  in  the  inflammatory  process.  Cripps  states  that 
vesicosigmoidal  fistula  is  more  commonly  inflammatory  than  ma- 
lignant (forty-five  out  of  sixty-three  cases).  If  such  be  the  case, 
many  of  them  may  be  the  result  of  a  diverticulitis.  Disturbed 
bowel  function  is  constant.  Manv  cases  record  constipation  as  a 
more  or  less  pronounced  prodromal  symptom.  Pelvic  abscess, 
tubo-ovarian  abscess,  mucous  colitis,  amebic  colitis,  chronic  proc- 
titis, tuberculosis  and  syphilis  of  the  sigmoid,  psoas  disease,  retro- 
peritoneal abscess  in  the  left  flank  from  other  causes,  etc.,  must, 
in  addition  to  the  conditions  already  mentioned,  be  differentiated. 
Treatment. — The  treatment  must  be  surgical  in  many  cases. 
The  prognosis  is  often  a  question  of  technical  efficiency.  It  is 
certain  that,  as  in  appendicitis,  many  of  the  cases  will  recover 
without  operative  interference.  Just  what  are  the  indications  for 
resection  in  hyperplastic  sigmoiditis  is  a  question  for  future  de- 
termination. Abscesses  and  vesicosigmoidal  fistulse  should  always 
have  the  advantage  of  surgical  treatment.  As  knowledge  of  the 
morbid  anatomy  of  false  diverticula  increases,  as  cases  are  recog- 
nized, reported,  and  treated,  as  methods  of  surgical  procedure 
become  crystallized,  facts  will  be  obtained  for  reliable  diagnosis 
and  prognosis. 

rp:ferences. 

Fischer :  Journal  Exper.  Med.,  1900,  v,  33. 

Beer:  Amer.  Jotir.  Med.  Sci.,  1904,  cxxviii,  135. 

Telling:  Brit.  Med.  Joicr.,  October  31,  1908,2496. 

Franke :  Deutsche  nted.  Woch.,  1909.  xxxv,  98. 

Eisendrath :  Arch.  Diag.,  October,  1909. 

Giffin  and  Wilson :  Amer.  Jour.  Med.  Sci.,  1909,  cxxxviii,  661. 


A  SIMPLE  METHOD  OF  CULTIVATING  THE  MORAX- 
AXENFELD  DIPLOBACILLUS. 


BY  WILLIAM    H.   PETERS,   M.D. 


The  following  note  calls  attention  to  the  fact  that  the  Morax- 
Axenfeld  bacillus  grows  as  readily  and  in  as  characteristic  manner 
on  Dorset's  egg  medium  as  upon  Loeffler's  blood  serum.  The 
comparative  ease  with  which  the  former  medium  can  be  prepared 
should  render  this  fact  of  value. 
To  cite  an  illustrating  case : 

James  M.  W.,  aged  thirty-four  years,  a  blacksmith,  was  ad- 
mitted into  the  service  of  Dr.  D.  T.  Vail  on  October  24,  1910. 
He  was  suffering  from  a  double  catarrhal  conjunctivitis  which  he 
thought  had  been  acquired  by  using  the  towel  of  his  roommate 
who  had  sore  eyes. 

Smear  preparations  from  the  purulent  secretion  from  each  eye 
showed  the  presence  of  isolated  diplobacilli  lying  between  the 
polymorphonuclear  leucocytes  and  apparently  in  pure  culture. 
The  diplobacilli  measured  2.7  x  3  fi  and  the  rods  had  rounded 
ends.  They  stained  well  with  Loeffler's  methylene  blue  but  lost 
the  stain  in  Gram's  method. 

Slants  of  Dorset's  egg  medium  and  Loeffler's  blood  serum 
were  inoculated  with  pus  from  each  eye.  After  twenty- four 
hours'  incubation  numerous  characteristically  pitted  colonies  ap- 
peared, resembling  those  described  by  Morax  (An.  de  VInst.  Past., 
1896,  10,  p.  337)  and  Pusey  (Journal  A.  M.  A.,  1906,  47,  p.  255). 

The  pits  in  Dorset's  egg  medium  were  not  quite  as  deep  and 
the  diameter  less  than  those  in  Loeffler's  l>lood  serum  and  they 
did  not  become  confluent  upon  the  former  medium  as  rapidly  as 
upon  the  latter.  Transplants  failed  to  grow  upon  the  ordinary 
laboratory  media. 


145 


THE    ELECTROCARDiUGRA-M.* 


BY  JOHN   E.  GREIWE,   M.D. 


In  attempting  to  analyze  the  rather  complicated  results  obtained 
by  means  of  the  electrocardiograph,  it  will  be  necessary  to  bear 
in  mind  that  in  the  heart  muscle  we  have  to  deal  with  tissue  which 
has  a  number  of  definite  functions  to  perform.  It  is  obvious  that 
we  are  dealing  with  muscular  tissue  whose  prime  function  is  that 
of  expelling  the  blood  into  the  greater  and  the  lesser  circulation. 
In  order  to  accomplish  this  end  to  greatest  advantage,  we  find 
that  there  is  a  constant  and  definite  arrangement  of  this  muscular 
tissue. 

Without  going  into  detail,  one  can  obtain  a  fair  idea  of  this 
complicated  structure  by  recalling  for  a  moment  the  component 
parts  in  the  distribution  of  heart  muscle  in  the  auricles  and 
ventricles. 

The  circular  muscle  fibres  found  at  the  mouth  of  the  superior 
vena  cava,  are  found  to  be  continuous  with  those  of  the  auricle. 
One  may  do  well  to  fix  in  mind  this  area  of  auricular  muscle 
fibres  at  the  mouth  of  the  superior  vena  cava,  since  we  find  here 
the  node  of  Keith,  in  which  the  normal  heart  stimulus  begins,  and 
furthermore  since  Wenkebach  calls  our  attention  to  the  fact  that 
he  has  found  this  area  to  be  the  seat  of  important  pathologic 
changes  which  he  believes  of  great  consequence  in  the  explanation 
of  heart  irregularities,  especially  in  connection  with  tricuspid  in- 
sufficiencies. 

The  auricles  have  each  their  own  separate  muscle  fibres,  which 
can  well  be  seen  through  the  thin  endocardium.  Then  there  are  a 
limited  number  of  fibres  common  to  both  auricles.  Of  special 
interest  in  the  auricle  is  that  strongly  developed  muscular  mass, 
the  auricular  appendage,  which  is  believed  to  have  much  to  do 
with  the  passing,  under  great  pressure,  of  the  last  few  drops  of 
blood  between  the  almost  closed  auriculo-ventricular  valves. 

The  distribution  or  arrangement  of  muscle  fibres  in  the  auri- 

*  From  The  Lancet-Clinic.  July  20.  1912. 

147 


148 


DANDRIDGE    MEMORIAL 


cles  is  comparatively  simple.  Not  so,  however,  in  the  ventricles. 
These  chambers  have  some  fibres  common  to  both,  and  again, 
there  is  a  distinct  system  of  fibres  for  each  ventricle.  We  may, 
however,  simplify  matters  by  bearing  in  mind  that  we  have  here: 

The  external  and  internal  longitudinal  or  spiral  muscle  fibres. 

The  circular  muscle  fibres. 

The  papillary  muscles. 

The  external  or  spiral  muscle  fibres  have  their  origin  at  the 
base  of  the  heart,  at  the  fibrous  ring  in  the  auriculo-ventricular 
septum.     They  pass  over  the  heart  diagonally,  viz. :    From  the 


Fig.  1. — Diagram  of  the  Muscular  System  of  Heart. 

base,  anterior  surface  (right  ventricle),  downward  and  outward 
to  the  left;  from  the  base  posteriorly  (left  ventricle),  downward 
and  inward  to  the  right.  They  end  in  the  whorl  at  the  apex  of 
the  heart. 

The  peculiar  distribution  of  the  circular  muscle  fibres  is  of 
special  interest  in  the  analysis  of  the  electrocardiogram.  It  should 
be  remembered  that  they  have  no  tendinous  attachments.  If  one 
can  speak  of  this  system  of  fibres  as  of  greater  importance  than 
any  other  it  is  because  of  its  strength  and  it3  function.  It  is 
to  this  system  of  circular  muscle  fibres,  so  well  developed,  and 
with  the  function  of  expelling  the  blood  from  the  ventricles  into 
the  large  arteries  at  the  base,  that  the  Germans  have  appropriately 
applied  the  term  "Das  Treibwerk  des  Herzens."  These  fibres  are 
not  found  exactly  at  right  angles  to  the  axis  of  the  heart,  but  they 


G  R  E  I  W  E.  149 

end  in  one  another  without  any  tendinous  attachments.  Attention 
will  be  called  to  their  position  in  the  electrocardiogram.  Of  more 
than  ordinary  interest  is  the  position  and  relation  of  the  papillary 
muscles  in  the  construction  of  the  ventricles.  The  stimulation  and 
contraction  of  the  papillary  muscles  is  not  only  well  seen  in  the 
electrocardiogram,  but  by  means  of  it  the  dispute  as  to  whether 
the  base  or  the  apex  of  the  heart  is  the  first  to  contract  seems 
to  be  definitely  settled.  We  see  that  the  stimulus  passes  from 
the  bundle  of  His  to  the  papillary  system  before  the  circular 
muscle  fibers  can  be  affected.     (  Figs.  1  and  2. ) 


CIRCULAR  §i    ^^l^h^     TO VENTRICLE 

MUSCLE 
FIBRES 

SPIRAL  MUSCLE  \^      '"^^W^T"      Wl       SPlRAt.  flUSCLS 

FIBRES  m        "^^^  m FIBRES 


Fig.  2. — Diagrammatic  Scheme  of  the  Heart  Stimuli    {after  Nikolai). 

I  have  here  given  very  briefly  the  relations  of  those  muscu- 
lar structures  which  are  engaged  in  passing  the  blood  from 
the  upper  into  the  lower  chatnbers,  and  with  the  expulsion  of 
this  same  mass  from  the  lower  chambers  into  the  great  vessels 
at  the  base  of  the  heart. 

It  will  be  seen  that  so  far  we  are  dealing  with  structures  whose 
main  function  is  that  of  contraction,  and  while  we  recognize  that 
the  muscle  fibers  have  other  important  functions,  we  know  now 
that  the  path  for  stimulus  lies  in  a  definite  system  of  fibers.  For 
the  purpose  of  our  study  it  is  necessary  to  call  to  mind  that  there 
is  in  the  normal  state  a  definite  connection  and  correlation  of 


150  D  A  X  D  R  I  D  G  E    M  E  M  O  R  1  A  L 

these  muscular  structures  just  considered,  and  that  there  is  a 
definite  path  of  communication  between  the  upper  and  lower 
chambers  of  the  heart. 

The  work  of  Ludwig,  His  and  Kent,  Aschoit  and  Tawara,  has 
thrown  much  hght  upon  the  muscular  structure  of  the  heart  and 
the  paths  of  stimulus  conduction. 

His  and  Kent,  in  1893,  called  attention  to  the  muscular  con- 
nection between  auricle  and  ventricle. 

Albrecht,  in  his  monograph  upon  the  heart  muscle,  demon- 
strated the  connection  between  the  papillary  system  and  the  cir- 
cular muscular  fibers,  and  more  recently  our  attention  has  been 
called  to  the  further  distribution  of  the  bundle  of  His  and  iis 
relation  to  the  fibers  of  Purkinje  in  the  walls  of  the  ventricle. 

It  is  the  fact  that  in  the  electrocardiogram  we  have  a  means 
of  analyzing  the  course  of  the  stimulus  through  this  intricate 
mass  of  muscle  tissue  in  normal  as  well  as  in  pathologic  condi- 
tions, which  makes  this  new  method  one  of  great  interest  to  the 
physiologist,  the  pathologist  and  the  clinician. 

\\'e  speak  of  the  stimulation  and  contraction  of  the  heart  as 
two  separate  functions.  They  must  be  so  considered.  Xevev- 
theless,  stimulation  and  contraction  are  so  closely  allied,  so  inti- 
mately related  in  time,  that  for  the  purpose  of  clinical  research 
they  may  in  a  sense  be  considered  as  occurring  simultaneously. 
It  is  generally  impossible  to  disconnect  these  two  functions  in  or- 
dinary cases,  such  as  would  come  to  the  obsen-ation  of  the  clini- 
cian. It  should  be  stated,  however,  that  some  recent  observations 
with  the  electrocardiograph  have  clearly  shown  the  electric  vari- 
ation waves  in  the  dying  heart  of  lower  animals,  when  active  con- 
traction had  ceased,  and  when  nothing  more  than  fibrillary  twitcli- 
ings  of  the  heart  muscle  could  be  detected. 

In  the  electrocardiogram  we  see  the  efifects  first,  of  auricular 
stimulation ;  next,  a  period  in  which  the  stimulus  passes  through 
the  bundle  of  His  between  auricle  and  ventricle ;  then  the  passage 
into  the  papillary  system ;  next  the  passage  through  the  circular 
muscle  fibers.  Immediately  following  this  is  seen  a  period  in 
which  the  stimulus  passes  from  the  region  of  the  apex  of  the 
heart,  by  means  of  the  external  fibers,  back  to  the  base  of  the 
heart. 


GREIWE.  151 

In  the  interpretation  of  most  features  of  the  normal  electro- 
cardiogram, investigators  have  for  the  most  part  agreed.  There 
are  still  many  features  which  must  be  cleared  up  before  we  can 
be  finally  satisfied.  These  relate  to  the  peculiarities  of  the  elec- 
tric phenomena  of  the  normal  variations,  and  more  especially  to 
those  cardiograms  obtained  from  pathologic  conditions.  In  this 
connection  it  may  be  well  to  call  attention  to  an  important  ob- 
servation of  A.  Samojloff,  who  after  stating  his  own  researches, 
and  after  analyzing  the  work  of  Waller,  Einthoven,  Krauss  and 
Nikolai,  says :  "Die  Akten  iiber  die  Auffassung  der  Entstehungs- 
weise  des  V'erlaufes  des  Electrokardiogrammes  sind  lange  noch 
nicht  geschlossen." 

However,  by  calling  to  mind  the  development  of  the  heart 
from  the  primitive  tube,  and  remembering  that  by  means  of  the 
curving  or  twisting  of  this  primitive  tube  we  have  the  sinus  and 
the  aortic  bulb,  two  extremes  of  the  tube,  brought  in  close  ap- 
position, and  furthermore  having  constantly  in  mind  the  path 
of  stimulus  conduction,  we  may  consider  ourselves  in  a  fair 
way  to  obtain  valuable  information  concerning  the  meaning  of 
the  electrocardiogram. 

Let  me  again  emphasize  the  fact,  that  although  it  is  plain  we 
are  dealing  with  the  release"  of  electric  energy,  it  is  not  quite  clear 
whether  this  release  of  energy  in  the  form  of  electrical  waves 
is  due  to  stimulation  or  contraction.  As  already  stated,  the  stim- 
ulus passing  through  a  dying  heart,  an  organ  in  which  active  con- 
tractions are  no  longer  manifest,  will  still  give  rise  to  a  well- 
marked  release  of  electric  energy.  It  is  possible  that  such  a  heart, 
in  which  only  fibrillary  contractions  are  seen,  is  still  attempting 
to  contract,  and  is  responding  to  the  stimulus  in  this  manner, 
and  that,  as  a  consequence  of  the  effort,  such  chemical  changes 
are  produced  which  result  in  the  electric  effect.  That  there  is 
a  decided  difference  in  normal  and  abnormal  cases  in  the  electro- 
cardiograms may  be  seen  in  such  cases  where  we  have  hypertro- 
phy of  certain  segments  of  the  heart.  It  is  well  known  that  the 
left  ventricle,  when  the  seat  of  degenerative  lesions  such  as  are 
seen  in  arrythmia  vera,  will  show  negative  variation  waves  which 
differ  most  decidedly  from  those  obtained  from  the  powerfully 
contracting  left  ventricle.     So,  too,  Krauss  and  Nikolai,  in  study- 


152 


D  A  N  D  R  I  D  G  E    MEMORIAL 


ing  the  electrocardiograms  from  cases  of  pure  mitral  stenosis, 
show  auricular  waves  so  well  marked,  so  prominent  in  the  elec- 
trocardiograms, that  one  can  safely  venture  a  diagnosis  of  ste- 
nosis of  the  mitral  orifice  from  the  appearance  of  the  cardiogram. 
(No.  III.)  We  may,  therefore,  from  a  practical  standpoint,  con- 
sider the   two   functions  of  stimulation   and  contraction  as   so 


Fig.  3 — After  Nikolai. 

closely  allied  that  in  the  electrocardiogram  they  may  be  consid- 
ered as  occurring  synchronously. 

In  the  electrocardiograph  we  have  an  instrument  of  precision 
for  measuring  the  release  of  electric  energy  from  the  function- 
ating heart.  The  whole  subject  is  a  study  of  negative  variation 
waves. 

A  tissue  whi'^h  is  absolutely  at  rest  is  referred  to  as  iso-elec- 
tric,  and  while  certain  tissues  of  the  body  may  for  a  time  be  at 
rest,  there  is  constantly  present,  somewhere  in  the  body,  activity 
of    various    organs,    and     more    particularly    of    the    constantly 


-.7- 

1 

>2 


W 


Electrocardiogram  No.  III. — Mitral  steno- 
sis with  marked  A  wave. 


G  R  E  I  W  E  153 

contracting  heart,  so  that  electric  waves  are  generated.  In  other 
words,  action  currents  are  constantly  being  generated,  and  by 
means  of  appropriate  instruments  such  action  currents  are  re- 
corded. Any  gland  in  function  or  any  muscle  in  contraction  will 
produce  action  currents.  It  may  be  important  in  connection  with 
the  analysis  of  the  action  currents  generated  in  the  heart,  to  bear 
in  mind  the  distinction  which  is  made  with  reference  to  the  dif- 
ferent effects  obtained  by  stimulating  and  recording  the  effects 
of  stimulation  and  contraction  in  a  muscle  which  is  contracting 
against  a  load  which  it  can  overcome,  and  the  contracting  of  a 
muscle  working  against  a  load  which  it  cannot  overcome. 

If  a  muscle  contracts  against  a  load,  and  a  shortening  of  the 
muscle  occurs,  we  are  dealing  with  what  physiologists  speak  of 
as  an  iso-tonic  contraction;  whereas,  if  the  muscle  contracts 
against  a  load  constantly  increasing  in  tension,  we  are  dealing 
with  iso-metric  contractions. 

Iso-tonic  contractions  show  negative  variation  waves,  and  iso- 
metric contractions  give  positive  variation  waves. 

Just  how  far  this  distinction  between  negative  and  positive 
waves  may  be  interpreted  from  the  point  of  view  of  their  being 
iso-tonic  or  iso-metric  remains  to  be  seen. 

The  recording  of  electric  waves  generated  by  the  contracting 
heart  is  not  new.  Physiologists  have  long  been  ?tcquainted  with 
the  work  of  Waller  in  experimenting  with  the  exposed  heart  of 
the  dog.  The  present  work,  however,  is  in  so  far  of  the  most 
practical  nature  that  we  are  able  to  make  use  of  the  former  re- 
search, and  by  means  of  the  Einthoven  string  galvanometer  we 
can  now  record  the  action  currents  of  the  human  heart,  using 
the  tissues  about  the  heart  and  the  extremities  of  the  body  as 
conductors. 

To  Waller,  therefore,  belongs  the  credit  of  demonstrating 
the  possibility  of  recording  electric  waves  generated  by  the  acting 
heart.  Waller  used  the  capillary  electrometer.  The  work  of 
Einthoven  is  based  upon  the  results  obtained  by  Waller,  but  the 
instrument  devised  by  Einthoven  is  much  more  delicate  and  re- 
sponds promptly  and  effectively  to  the  finest  possible  variations 
of  the  electric  waves  generated  in  the  heart.  Waller  called  atten- 
tion to  the  diagonal  position  of  the  heart  as  giving  rise  to  the  pos- 


154 


DANDRIDGE    MEMORIAL 


nihility  of  recording  the  difference  in  potential  between  base  and 
apex  of  the  heart. 

The  heart  in  its  diagonal  position  is  sending  currents  from 
base  and  apex  to  the  right  and  left  halves  of  the  body  or  to  the 
upper  and  lower  parts  of  the  body. 

The  well-known  figure  by  Waller,  showing  the  difference  in 
electrical  potential,  will  be  found  in  all  the  recent  text-books  on 
physiology. 

The  third  figure,  worked  out  more  definitely  by  Nikolai,  gives 
the  values  in  figures,  and  reference  to  the  latter  scheme  will  show 


II  i 


Fig.  4. — Diagrammatic  Scheme  of  the  Electrocardiogram   {after  Nikolai). 

H,  His  bundle;  T,  circular  muscle  fibers — Treibwerk;  A,  auricular  wave, 
J,  initial  ventricular  wave ;  F,  final  ventricular  wave. 

that  the  greatest  difference  in  potential  can  be  obtained  by  con- 
ducting from  the  mouth  and  anus.  For  convenience  sake,  how- 
ever, a  very  decided  difference  in  potential  can  be  obtained  by 
conducting  from  the  right  arm,  giving  a  — 4,  and  the  left  leg, 
giving  a  +3.  Even  this  is  somewhat  inconvenient,  and  for  clin- 
ical and  practical  purposes,  when  the  right  arm  and  left  arm  are 
used,  we  still  get  a  difference  of  — 4  and  -\-2.  It  has  been  sug- 
gested that  in  important  cases  one  take  measurements  both  as 
manifested  in  cardiograms  from  the  right  arm  and  left  leg  as 
well  as  from  both  arms.     (Fig.  3.) 

When  one  considers  how  rapidly  the  stimulus  passes  through 
the  complicated  heart  structure,  it  will  be  seen  that  by  the  time 
the  electric  effects  have  passed  by  means  of  the  surrounding 


GREIWE  155 

structures  to  the  surface  of  the  body,  the  instrument  for  record- 
ing such  delicate  waves  must  be  exceedingly  fine  and  exact.  It 
must  have  the  necessary  delicacy  to  respond  promptly  to  all  the 
finer  impulses.  It  must  above  all  else  be  aperiodic.  To  meet 
these  delicate  requirements  Einthoven  has  constructed  an  instru- 
ment which  differs  from  the  usual  galvanometer.  The  great  dif- 
ference, among  others,  is  that  whereas  in  the  ordinary  galvanom- 
eter the  magnet  is  the  movable  part,  and  the  current  passes  through 
the  spools,  the  contrary  is  the  case  in  the  Einthoven  instrument. 
Here  the  current  passes  through  the  delicate  thread,  and  the  mag- 
net is  fixed  as  in  the  D'Arsonval  galvanometer.  The  string,  a 
quartz  fiber  coated  with  silver,  has  the  thickness  of  0.001  to  0.003 
mm.  This  deHcate  thread,  suspended  by  its  ends  in  the  middle 
of  an  electro-magnetic  field,  when  stimulated,  vibrates  Hke  the 
string  of  a  string  musical  instrument.  This  thread  is  an  exceed- 
ingly good  conductor,  and  because  of  its  extreme  delicacy  is  found 
to  have  practically  no  weight.  As  a  matter  of  fact,  the  thread  is 
so  delicate  that  it  can  scarcely  be  seen  with  the  naked  eye,  and 
because  of  this  it  is  illuminated  by  means  of  the  arc  light  and 
magnified  by  means  of  the  projection  microscope. 

The  construction  of  the  Einthoven  string  galvanometer  is  a 
niosi:  complicr'ted  aft'air,  and  to  those  who  are  interested  it  may 
be  well  to  refer  to  the  brochure  by  Edelman,  Jr.,  of  Munich. 
The  essential  parts  of  the  instrument  are : 

1.  A  delicate  platinum  thread  or  quartz  fiber  coated  with  sil- 
ver, suspended  in  the  middle  of  an  electro-magnetic  field. 

2.  This  thread  is  under  the  control  of  a  micrometer  screw,  in 
order  to  control  its  tension. 

3.  It  is  connected  with  electrodes  coming  from  some  parts  of 
the  body,  which  will  allow  one  to  receive  the  current  generated 
by  the  contracting  heart. 

4.  The  strength  of  the  electro-magnetic  field  is  always  under 
control,  so  that  the  weakest  currents  generated  by  the  heart  can 
be  recorded. 

Furthermore,  the  thread,  being  practically  invisible  to  the 
naked  eye,  is  illuminated  by  means  of  ihe  arc  light,  and  then, 
by  means  of  a  projection  microscope,  enlarged  and  thrown  upon 
the  screen,  or  against  an  aperture  in  a  photographic  instrument. 


156  DAN  BRIDGE    MEMORIAL 

It  is  necessary  to  state  also,  that  not  the  whole  thread,  but  only- 
one  small  point  of  the  vibrating  string  is  photographed  in  its 
movements.  The  string  being  placed  vertically,  is  seen  to  vibrate 
in  that  position.  The  slit  in  front  of  the  sensitive  film  is  placed 
horizontally,  and  therefore,  as  the  film  unrolls  itself  vertically, 
we  have  this  one  small  point  photographed  as  a  shadow,  with  the 
result  as  seen  in  the  annexed  electrocardiograms.  (Nos.  I  and  II.). 

These  electrocardiograms,  taken  from  strong  normal  individ- 
uals, will  be  seen  to  have  certain  points  in  common,  although 
there  must  have  been  some  little  difference  in  the  tension  of  the 
string  or  in  the  strength  of  the  electro-magnetic  field. 

Another  great  advantage  in  the  electrocardiograph  of  Ein- 
thoven,  consists  in  the  fact  that  one  can  measure  the  action  cur- 
rent of  the  body  generally,  and  then  by  sending  in  a  counter- 
current  of  like  strength  one  is  enabled  to  deal  with  the  eft'ects  of 
the  heart  current  alone. 

One  may  be  permitted  at  this  point  to  call  attention  to  a  few 
general  laws  in  electro-physiology,  since  they  are  essential  in  the 
proper  understanding  of  the  electrocardiograms. 

Every  striped  muscle  in  contraction,  as  well  as  every  gland 
tissue  in  action,  gives  rise  to  chemical  changes  as  well  as  chemi- 
cal effects.  The  measure  of  the  difference  in  electrical  potential 
in  two  different  parts  of  the  structure  is  referred  to  as  the  action 
current.  Furthermore,  in  every  electrically  excitable  substance, 
the  point  of  excitation  is  at  the  moment  of  excitation  electro- 
negative, while  at  the  same  time  all  other  points  of  that  excitable 
tissue  are  considered  electro-positive.  It  will  be  seen  that  a  num- 
ber of  conditions  may  arise  here.  If  we  had  the  excitation  at  a 
definite  point,  remaining  here  and  not  passing  on,  simply  increas- 
ing in  intensity  and  then  dying  out,  we  would  have  a  so-called 
monophasic  curve.  Such  a  condition  evidently  does  not  obtain 
in  the  human  heart,  for  we  have  here  not  only  the  function  of 
excitability  but  also  that  of  conductivity,  so  that  a  given  point 
of  the  heart  muscle  is  at  the  moment  of  excitation  electro-nega- 
tive, but  the  excitation  in  passing  on  would  render  the  newly  ex- 
cited points  electro-negative  and  leave  the  first  point  of  stimu- 
lation positive.  We  are  therefore  dealing  no  longer  with  mono- 
phasic  but  with  diaphasic  curves  in  the  electrocardiogram. 


> 


u: 


w 


GREIWE  157 

In  the  electrocardiograph  of  Einthoven  the  right  and  left 
arms  are  immersed  in  a  salt  solution,  and  the  current  is  then  in 
an  appropriate  manner  conveyed  to  the  quartz  film  in  the  middle 
of  the  electro-magnetic  field.  With  each  contraction  of  the 
heart  one  notices  upon  the  screen  the  vibration  of  the  delicate 
thread.  A  study  of  the  electrocardiogram  reveals  the  fact  that 
We  have  a  definite  series  of  waves  recorded,  sho\ving  in  the  first 
place  the  regular  path  of  heart  stimulation  and  contraction ;  next, 
one  gets  a  good  idea  of  the  tone  or  strength  of  the  contraction, 
not  only  of  the  heart  as  a  whole,  but  of  its  component  parts;  one 
is  able,  furthermore,  to  recognize  the  evidence  of  myo-degenera- 
tions,  of  arrhythmias,  of  heart-block,  of  extra  systoles  and  their 
probable  origin. 

A  glance  at  electrocardiograms  Xos.  I  and  II  will  show  at  once 
that  there  are  three  distinct  waves  present  in  the  normal  condition. 
The  very  small  serrations  are  due  to  unavoidable  twitching  of 
muscle.  They  may  be  neglected  in  the  analysis  of  the  electro- 
cardiogram. It  has  been  definitely  established  that  the  first  ele- 
vation is  due  to  activity  of  the  auricle,  whereas  the  second  and 
third  elevations  are  ascribed  to  ventricular  action. 

These  elevations  have  been  referred  to  by  Einthoven  and  the 
majority  of  writers  upon  this  subject  as  respectively  the  P.,  R. 
and  T.  elevations,  the  P.  elevation  being  of  auricular  origin  and 
the  R.  and  T.  elevations  arising  from  the  ventricles.  There  can 
no  longer  be  any  question  as  to  the  correctness  of  these  views, 
since  Samojloflf  demonstrated  in  the  animal  heart  the  effects,  first, 
of  stimulation  from  auricle  and  ventricle,  and  then,  after  obtain- 
ing his  cardiogram  in  this  manner,  followed  by  stimulating  the 
ventricles  alone,  without  auricle  excitation,  obtaining  only  in  the 
second  experiment  the  R.  and  T.  waves  without  any  evidence  of 
the  auricular  wave. 

Thus  far  all  are  agreed  as  to  the  results  to  be  read  in  the 
electrocardiograms.  The  P.  waves  of  Einthoven  are  thus  seen 
to  be  due  to  auricular  action.  Immediately  after  the  P.  elevation 
one  notices  a  very  small  period  of  rest,  between  the  P.  wave  and 
the  R.  wave.  According  to  the  researches  of  Nikolai,  we  are  to 
look  upon  this  period  of  the  electrocardiogram  as  indicating  the 
passage  of  the  stimulus  through  the  bundle  of  His  from  the  auri- 


158  DANDRIDGE    MEMORIAL 

cle  to  the  ventricle.  The  stunulus,  according  to  the  now  accepted 
views  of  physiologists,  then  passes  to  the  papillary  system,  and 
at  once  a  powerful  contraction  takes  place,  resulting  in  the  very 
pronounced  R  wave,  a  wave  called  by  Nikolai,  in  his  newer  des- 
ignation as  the  Y  wave,  or  the  initial  ventricular  wave. 

Having  passed  through  the  papillary  system,  the  next  effect 
should  be  expected  from  the  now  known  path  of  conduction  in 
a  contraction  of  the  circular  muscle  fibers,  from  the  Treibwerk, 
as  designated  by  the  Germans.  The  circular  muscle  fibers  are 
peculiarly  situated,  and  we  are  told  that  the  dift'erence  in  poten- 
tial does  not  express  itself  in  the  electrocardiogram.  These  fibers 
have  no  tendinous  attachments,  they  end  in  one  another,  and  are 
in  a  measure  continuous  with  one  another.  The  result  is  that  we 
have  in  the  electrocardiogram  a  comparative  period  of  rest,  or 
at  least  a  period  not  expressed  by  a  distinct  elevation.  We  are 
to  look  upon  the  straight  line  between  the  R  and  T  elevations  as 
expressing  the  time  of  activity  of  the  circular  muscle  fibers  of 
the  heart. 

Immediately  after  this  period  we  get  the  final  ventricular  con- 
traction in  the  elevation  T,  which  expresses  the  time  of  the  pass- 
age of  the  stimulus  from  apex  back  to  base  of  heart. 

Nikolai  proposes  to  alter  the  terms  P,  R  and  T  elevations, 
and  designate  these  periods  by  terms  which  are  at  the  same  time 
immediately  expressive  of  what  is  actually  occurring.  (Electro- 
cardiogram No.  II.) 

It  will  be  of  interest  here  to  give  the  diagrammatic  representa- 
tion of  the  electrocardiogram  according  to   Nikolai.      (Fig.  4.) 

The  further  advantage  of  such  figures  may  be  that  of  fixing 
in  mind  the  path  of  the  heart  stimulus  and  the  successive  events 
in  the  cardiac  cycle. 

Through  the  courtesy  of  Prof.  Krauss  and  Dr.  Nikolai  it  was 
my  privilege  to  spend  a  short  time  in  the  laboratory  of  the  Charite 
in  Berlin.  During  that  time  experiments  were  being  made  prin- 
cipally upon  patients  who  were  the  subjects  of  valvular  lesions. 

It  is  remarkable  to  note  with  what  exactness  certain  features 
were  constantly  found  to  repeat  themselves  in  cases  of  mitral 
stenosis,  mitral  regurgitation,  aortic  regurgitation,  etc.  More 
especially  is  this  true  with  reference  to  the  hypertrophy  of  the 


GREIWE  159 

auricle  in  mitral  stenosis,  which  may  be  seen  in  the  electrocardio- 
gram No.  III. 

The  auricular  wave  is  exaggerated,  and  it  is  almost  as  well 
expressed  as  the  initial  ventricular  wave.  It  is  so  constant  a  fea- 
ture in  uncomplicated  cases  of  mitral  stenosis,  that  the  diagnosis 
was  made  from  the  cardiogram,  and  then  finally  confirmed  by  the 
later  physical   examination. 

In  cases  of  uncomplicated  mitral  regurgitation  there  was 
found  present  a  condition  as  shown  in  electrocardiogram  No.  IV. 

There  is  a  most  marked  drop  after  the  R  wave,  or  the  initial 
ventricular  wave  of  Nikolai.  The  final  wave  in  this  case  is  clear 
and  distinct,  and  may  be  taken  as  a  sign  of  perfect  compensation 
on  the  part  of  the  left  ventricle.  Just  why  the  drop  below  ihe 
base  line  should  occur  is  not  clear.  There  is  still  much  dispute 
as  to  the  origin  and  meaning  of  this  efifect,  and  further  time  must 
be  given  to  its  elucidation.  I  give  here  another  electrocardio- 
gram from  a  case  of  myo-degeneration,  showing  the  weakness 
of  the  whole  heart,  and  more  particularly  degeneration  in  the 
ventricles.i  We  have  here  not  only  an  arrhythmia  as  to  time,  but 
also  as  to  strength  and  tone  of  the  ventricle.     (Fig.  V.) 

The  results  of  work  wath  the  cardiogram  so  far  demonstrate 
that  it  will  not  only  be  used  in  physiological  laboratories,  but  a 
sufficient  number  of  important  clinical  observations  have  been 
made,  more  particularly  by  Krauss  and  Nikolai,  to  assure  us  of  its 
proper  field  in  clinical  medicine. 

A  complete  review  of  the  literature  and  an  exhaustive  work, 
theoretic  part  by  Nikolai  and  clinical  part  bv  Krauss.  has  just  ap- 
peared in  the  German  press.  The  work  emphasizes  the  impor- 
tance of  the  electrocardiogram  from  the  standpoint  of  the  physi- 
ologist and  the  clinician  as  well. 


THE  OVA  OF  SCHISTOSOMA  JAPONICUM  AND  THE 
ABSENCE  OF  SPINES.* 


BY  PAUL  G.  WOOLLEY^  M.D.,  AND  OTTO  V.  HUFFMANN^  M.D. 


The  observations  recently  set  forth  by  Dr.  Leiper^,  and  by  Dr. 
Sambon  in  a  discussion^,  have  led  us  to  re-examine  the  ova  of 
6'.  japonicum  in  the  material  which  we  have  at  hand.  This  ma- 
terial was  described  previously  by  one  of  us-  together  with  a 
report  of  some  comparative  measurements  of  the  ova  of  this 
species  of  trematode  furnished  by  Dr.  Shiga. 

We  have  now  re-examined  carefully  several  hundred  ova  in 
stained  sections  of  tissues  and  a  great  number  of  others  which  we 
have  teased  free  from  unstained  tissues  which  have  been  well 
preserved  in  Kaiserling's  solution.  In  no  instance  did  we  find 
the  least  appearance  of  a  blunt  protuberance  or  spine  on  the  outer 
envelope  of  the  egg.  In  one  or  two  instances  the  embryo  itself 
caused  a  slight  protuberance  about  the  size  of  the  spine  repre- 
sented in  Dr.  Leiper's  microphotograph,  but  without  any  of  the 
other  characteristic  points  reported  by  Dr.  Leiper — for  instance 
the  thickening  of  the  envelope  about  the  protuberance. 

When  examining  the  ova  of  5".  nmnsoni  we  have  never  ex- 
perienced any  difficulty  in  recognizing  the  lateral  spines,  and  if 
the  blunt  lateral  spine  of  5".  japonicum,  as  depicted  by  Dr.  Leiper, 
is  a  distinctive  characteristic  we  should  have  been  able  to  recog- 
nize it  in  the  present  series  of  examinations,  even  though  we  had 
overlooked  it  in  an  equally  large  number  of  examinations  upon 
which  our  original  measurements  were  based. 

With  regard  to  the  similarity  of  these  ova  and  those  of 
'Anchylostoma  diiodetiale:  the  ova  of  the  latter  are  more  nearly 
ovoid,  while  those  of  5*.  japonicum  are  somewhat  flattened,  so 

*From  Parasitology,  vol.  iv,  No.  2,  July  18,  1911. 

161 


162  DA  >' BRIDGE     MEMORIAL 

that  we  would  hardly  speak  of  rolling  them  under  the  cover  glass 
but  rather  of  turning  them  over. 

REFERENCES. 

1.  Leiper,  R.  T.  Cm,  1911).  Note  on  the  presence  of  a  lateral  spine  in 
the  eggs  of  Schistosomum  japonicum.  Trans.  Sec.  Trop.  Med.  and  Hyg. 
iv,  p.  133.     (Discussion,  p.  135.) 

2.  WooUey,  P.  G.  (i.  1906).    The  occurrence  of  Schistosoma  japonicuni 
vel  cattoi  in  the  Philippine  Islands.    Philippine  Journal  Science,  i,  p.  83. 


HAIRY  OR  BLACK  TONGUE.* 


BY    M.    L,    HEIDINGSFELD,    M.D. 


The  subject  of  hairy  or  black  tongue  has  engrossed  a  varied  de- 
gree of  attention  in  dermatologic  Hterature.  A  comparatively 
large  number  of  the  cases,  chiefly  from  French  and  English 
sources,  were  reported  at  the  time  of  the  discovery  and  early 
mention  of  the  affection.  Brosin^  recorded  some  forty  odd  cases 
reported  prior  to  1888.  The  next  large  increment  of  cases  oc- 
curred when  investigators  first  took  issue  in  regard  to  its  para- 
sitic or  non-parasitic  nature,  which  has  remained  a  more  or  less 
unsettled  point  of  contention  to  the  present  day.  Relatively  few 
cases  have  been  reported  in  recent  years,  not  so  much  because  the 
affection  is  possibly  more  rare  or  exceedingly  infrequent,  as  be- 
cause little  additional  infonnation  could  be  offered  regarding  its 
etiology,  pathology  and  treatment.  There  are  scarcely  a  hundred 
cases  recorded  in  the  literature  at  the  present  time,  and  if  the 
spurious  and  unauthenticated  cases  were  eliminated  the  remain- 
der would  probably  not  total  much  more  than  half  that  number. 
The  earliest  report  of  the  affection  probably  emanates  from 
Rayer,-  who  in  1835  described,  under  the  name  discolorations  pig- 
inentaires,  several  cases  of  black  discoloration  of  the  dorsal  sur- 
face of  the  tongue.  Eulenberg^  in  1853  described  a  black-coated 
tongue  {eine  schwarae  Zwigenbeiag)  in  a  two-year-old  child  af- 
fected with  diarrhea,  which  persisted  for  several  months.  He 
first  called  attention  to  involvement  of  the  filiform  papillae,  a  fea- 
ture more  carefully  elaborated  later  by  Gubler.*  St.  Germain^' 
in  1855  reported  some  transient  cases  of  short  duration  in  de- 
bilitated individuals,  under  the  name  nigrite  de  la  langue.  Ray- 
naud*' in  1869  independently  described  several  cases  as  a  new  af- 

*  Read  in  the  Section  on  Dermatology  of  the  American  Medical  Asso- 
ciation, at  the  sixty-first  annual  session,  held  at  St.  Louis,  June.  1910,  and 
reprinted  from  The  Journal  of  the  American  Medical  Association,  Decem- 
ber 17,  1910,  vol.  Iv,  pp.  2117-2123. 

163 


164  DANDRIDGE    MEMORIAL 

fection,  and  first  ascribed  the  condition  to  a  parasitic  cause.  He 
pictured  mycelia  and  spores  unlike  any  previously  described.  As 
soon  as  Raynaud  attributed  a  parasitic  etiology,  interest  in  the 
affection  materially  increased.  Gallois^  was  unable  to  confirm 
Raynaud's  observations,  and  Richter^  states  that  he  had  observed 
the  tongue  epithelium  to  develop  into  thick,  black,  cylindrical 
"turf"  (Rasen)  without  ever  being  able  to  discover  Raynaud's 
fungus.  FereoP  likewise  found  no  evidence  of  spores  in  his 
case  and  stated  that  their  presence  in  hairy  tongue  must  be  of 
accidental  rather  than  etiologic  character.  He  considered  the 
hypertrophy  of  the  filiform  papillae  the  essential  pathologic  fea- 
ture, and  called  the  affection  I'hypertrophie  epitheliale  filiforme. 
Within  a  few  years  Laveau,^"  Lan^.ereaux^^  and  Dessois^-  reported 
some  cases  with  which  they  confirmed  Raynaud's  parasitic  etiol- 
ogy. Dessois  attempted  to  confirm  the  parasitic  nature  of  the 
affection  by  inoculation  experiments  on  his  own  tongue,  which, 
however,  proved  negative  in  character.  He  named  the  affection 
glossophytie.  Rayer  reported  that  not  only  were  inoculation  ex- 
periments negative,  but  morphologically  similar  spores  were  pres- 
ent on  normal  tongues.  Pellarez,^^  a  Spaniard,  erroneously  re- 
garded the  condition  as  a  vegetating  growth,  and  Salter^*  as- 
cribed the  discoloration  to  an  anomaly  of  pigmentation.  Butlin" 
believed  the  fungi  normally  found  in  the  mouth  could,  under 
special  conditions,  impart  a  black  discoloration  to  the  coating  of 
a  tongue.  Schech^®  described  the  discoloration  under  the  micro- 
scope as  light  to  dark  brown  and  diffusely  distributed  over  the 
hairs,  without  being  interspersed  with  sharp,  distinct  accumula- 
tions of  pigment  or  areas  free  from  pigment.  The  hairs  con- 
sisted of  thickly  crowded  masses  of  long,  thin  epidermic  cells, 
with  a  marked  tendency  to  bristle  and  branch  at  the  borders. 
They  set  forth  the  greatly  enlarged,  cornified  and  pigmented  fili- 
form papillae.  A  remarkable  feature  was  the  absence  of  fine 
granular  masses  of  cocci,  bacilli  and  leptothrix,  which  are  a  part 
of  the  normal  coating  of  the  tongue.  Schech  found  no  evidence 
of  fungi  to  support  Dessois,  and  Sell  was  obliged  to  retract  his 
former  expressed  views  regarding  its  myotic  character.  Brosin^ 
regarded  the  affection  as  a  hypertrophy  of  the  papillae  filiformes, 
with  abnormal  pigmentation  and  keratosis  of  the  affected  tissue. 


Fk;.  1. — SpeciniL'ns  from  patient  with  hairy  or  lihick  tongue:  A,  separated 
from  each  other  at  the  extremity;  appearance,  tuft -like;  a  single  hair 
composed  of  several  clcsely  united  shafts;  B,  stained  hair  of  consider- 
al)le  size;  C.  unstaired  lilament  coated  with  loose  masses,  composed 
largely  of  micro-organisms;  D.  hair  resembling  in  appearance  a  stalk 
of  Indian  corn;  K,  one-half  of  hair  measuring  three-fourths  inch;  ten- 
fold magnification. 


HEIDINGSFELD  165 

This  view  was  supported  by  Rosenberg/^  Rydygier/^  WoUer- 
and/"  Surmond-'^  and  others,  and  their  studies  revealed  the  pres- 
ence of  many  forms  of  micro-organisms  of  incidental  and  non- 
pathogenic significance. 

Those  who  have  confirmed  the  parasitic  nature  of  the  affec- 
tion in  more  recent  years  are  Roth,-^  who  found  a  micro-organ- 
ism abundantly  present  in  two  cases,  to  which  he  attributed  the 
discoloration,  and  called  the  affection  a  keratomycosis.  Dinkier-^ 
disclosed  the  presence  of  a  filiform  bacillus,  but  was  unable  to 
cultivate  it.  Lake"^  detected  the  presence  of  round  spores.  Ciag- 
linski  and  Hawelke^*  and  Sendziak-'^  were  able  to  cultivate  a 
black  fungus  to  which  they  attributed  etiologic  importance,  but 
only  at  room — not  at  body — ^temperature.  Rosiowjew-®  describes 
in  his  two  cases,  in  addition  to  the  ordinary  mouth  bacteria,  a  pecu- 
liar cladothrix,  the  cultures  of  which  were  black.  Much  infec- 
tious significance  is  attributed  by  Rostowjew  to  the  occurrence  of 
the  affection  in  husband  and  wife.  GottheiP^  illustrates  the 
spores  in  his  case,  which  showed  only  a  black  discoloration  of 
the  tongue,  without  a  coat  of  hair-like  prolongations.  Lucet-^ 
describes  the  presence  of  small  round  or  oval  double  contoured, 
highly  refractive  bodies,  with  hyaline  or  finely  granular  contents. 
They  stained  with  compound  solution  of  iodine  and  grew  luxuri- 
antly on  5  per  cent,  glucose  agar  at  '^7°  C.  Inoculation  experi- 
ments on  rabbit  tongues  were  negative.  Gottheil  named  the  fun- 
gus Sac  char  omyces  linguce  pilosoR.  Gaston  and  Laselet"*  believed 
that  the  cause  of  the  black  discoloration  was  a  fungus  which  they 
successfully  cultivated.  Gueguen^°  is  the  latest  observer  to  at- 
tribute this  affection  to  a  hitherto  undescribed  organism,  the 
Oospora  lingiialis.  Equally  large  is  the  number  of  present-day 
observers  and  investigators  who  either  ignore  or  regard  as  unten- 
able the  theory  of  the  parasitic  origin  of  the  affection  and  attrib- 
ute it  to  other  causes.  Levisseur^^  attributed  the  cause  in  his 
case  to  use  of  silver  nitrate  and  chromic  acid  in  the  treatment  of 
syphilitic  plaques.  SchnabeP^  and  Schourp^^  regard  the  affection 
as  a  common  one  among  syphilitics,  dyspeptics  and  tobacco  users. 
Audry  and  Dalous^"*  and  Hallopeau^^  have  observed  the  affection 
in  cases  of  Darier's  disease.  Mourek,^^  in  his  carefully  reported 
and  investigated  case,  states  that  micro-organisms  were   found 


166  DANDRIDGE    MEMORIAL 

sparingly  and  gave  no  evidence  of  anything  of  characteristic  sig- 
nificance. The  bacteriologic  investigation  was  of  negative  char- 
acter. He  believed  the  process  is  a  hyperkeratosis  and  the  dis- 
coloration the  result  of  contact  with  food  and  other  extraneous 
products.  The  epithelial  cells  cohered  and  became  mechanically 
discolored,  as  in  other  keratotic  affections  of  the  skin.  Vollmer^^ 
states  that  though  the  etiology  and  mode  of  production  are  ob- 
scure, he  is  of  the  opinion  that  syphilis,  mercuriaiization,  strong 
disinfectants,  tobacco,  etc.,  are  predisposing  factors.  He  regards 
the  parasitic  etiology  as  untenable. 

REPORT   OF   CASES. 

Case  L— On  May  25,  1909,  Mr.  A.  D.,  aged  eighty-five,  was 
referred  to  my  attention  for  a  peculiar  discoloration  of  the 
tongue,  v/hich  was  the  site  of  severe  subjective  pam  and  discom- 
fort. Examination  revealed  a  brownish-black  discoloration  ex- 
tending anteriorly  from  the  circumvallate  papilla  to  within  al- 
most one  inch  of  its  tip  and  one-half  inch  of  the  right  lateral  bor- 
der. The  affected  area  was  irregularly  elliptical  in  outline,  situ- 
ated for  the  most  part  on  the  right  side  of  the  tongue,  but  slightly 
transgressed  the  median  line  at  its  middle  third.  The  patch  was 
black  at  its  center,  with  borders  that  gradually  faded  from  brown- 
ish-black to  yellowish  brown.  The  remainder  of  the  tongue  and 
the  mucous  membranes  of  the  mouth  were  bright  red  and  normal 
in  appearance.  Salivation  was  very  marked,  and  the  patient  com- 
plained severely  of  intense  pain  in  the  tongue,  which  v^-as  also  re- 
ferred to  the  ears.  The  patch  was  thickly  covered  with  a  soft, 
felt-like  coating  of  hair-like  processes,  which  on  more  careful 
examination  and  inspection  were  found  to  be  inextricably  inter- 
woven and  matted  together,  in  the  manner  of  "a  field  of  grain 
laid  low  by  storm  and  wind,"  as  previously  described  by  Gubler, 
Raynaud,  Stokes  and  Lake.  An  abundance  of  long  hairy  fila- 
ments, some  of  which  measured  three-fourths  of  an  inch  in  length, 
could  be  readily  removed  with  thumb  forceps.  The  patient,  an 
intelligent  German,  stated  that  his  personal  attention  was  first 
directed  to  his  tongue  some  two  months  prior  to  the  time  of  the 
examination,  by  pain  and  a  sense  of  soreness  in  the  tongue,  and 
the  black  discoloration  was  then  in  evidence  in  its  present  un- 
changed form.  No  history  of  its  incipiency  or  probable  duration 
was  obtainable. 

Biopsy. — On  May  28  a  biopsy  was  made  for  histologic  study. 
Patient  was  observed  daily.  The  pain  became  more  intense  and 
salivation  more  marked.     On  June  3  a  marked  swelling  mani- 


Fic;.  2. — Hair-like  tilameiits  cut  vertically  and  longitudinall}-  to  their  long 
axis.  Many  intertwined  filaments  cut  obliquely  and  transversely.  Fila- 
ments reach  ujnvard  and  forward  in  irregular  parallels. 


Fig.  3. — Papilla-like  bodies   within   the   rete   Malpis^hii  :   pro])al)le  origin   n 
hair-like   filaments. 


H  E  I  D  I  N  G  S  F  E  L  D  167 

fested  itself  at  the  left  lateral  border  of  the  tongue  near  its  mid- 
dle third  and  remote  from  the  hairy  involvement ;  the  mass,  which 
was  deep-seated  in  origin,  was  firm  and  hard  in  consistence,  ir- 
regular in  outline.  The  lesion  was  diagnosed  as  an  epithelioma 
and  the  case  referred  to  a  surgeon.  The  subsequent  history  con- 
firmed this  diagnosis.  As  soon  as  ulceration  took  place  the  pa- 
tient experienced  some  sense  of  relief  from  his  distressing  pain. 
On  February  15,  1910,  the  bed-ridden  patient  was  still  alive,  al- 
though the  disease  had  made  great  inroads  on  his  previous  fairly 
robust  constitution ;  death  eventually  took  place  March  5,  1910. 
The  complicating  malignant  growth  in  this  case  was  without  ques- 
tion a  mere  coincidence,  and  has  its  analogue  in  the  case  of  a 
forty-nine-year-old  brickmaker,  reported  by  Lediard,  who  had 
an  epithelioma  at  the  tip  of  the  tongue,  remote  from  the  patho- 
logic hairy  area. 

Case  II. — R.  K.,  aged  nineteen,  was  first  seen  in  consultation 
April  6,  1905.  Patient  stated  that  three  months  previously  he 
noted  an  abnormal  sensation  in  the  tongue,  resembling  the  pres- 
ence of  a  foreign  body  on  the  surface  which  could  not  be  dis- 
lodged. On  looking  into  a  mirror  he  noted  for  the  first  time  the 
black  discoloration,  became  alarmed  and  forthwith  brought  the 
condition  to  the  attention  of  his  physician.  The  examination  re- 
vealed an  intense  blackish  discoloration  of  the  tongue,  with  bor- 
ders imperceptibly  fading  to  brownish-yellow,  occupying  a  tri- 
angular area,  extending  from  the  circumvallate  papillae  anteriorly 
along  the  median  dorsal  surface  of  the  tongue  almost  to  its  tip 
and  lateral  borders.  The  same  soft  felt-like  coating  of  matted 
hair-like  processes  was  observed  as  in  the  previous  case,  and  a 
specimen  was  removed  and  preserved  in  alcohol  for  histologic 
examination.  Pain  and  distress  were  entirely  absent,  and  there 
were  no  subjective  symptoms  except  as  already  noted.  Patient 
was  last  observed  on  January  15,  1910,  and  during  the  interven- 
ing five  years  no  appreciable  change  was  detef^ted  in  the  clinical 
appearance  of  the  tongue.  Patient  persistently  refused  a  biopsy, 
but  readily  permitted  the  removal  of  large  numbers  of  hairy  pro- 
cesses, some  of  which  measured  fully  three-fourths  of  an  inch 
in  length.  Syphilis  was  absent,  and  there  was  no  history  of  drug- 
taking  or  the  use  of  caustic  or  astringent  applications. 

In  addition  to  these  two  well-defined  clinical  cases,  it  has  been 
my  privilege  to  observe  several  rases  of  less  marked  character  in 
connection  with  conditions  of  general  dermatologic  interest.  The 
patients  were,  almost  without  exception,  unaware  of,  or  at  least 
indifferent  to,  the  manifestations  on  the  part  of  the  tongue,  which 
were  revealed  merely  by  process  of  routine  examination,  and 


168  DANDRIDGE    MEMORIAL 

doubtless  would  have  been  dismissed  with  passing  notice  had  not 
the  unusual  interest  of  the  condition  been  understood.  In  most 
cases  there  was  at  least  a  moderate  amount  of  felt-like  covering, 
of  hairy  growth,  in  addition  to  the  brownish  or  blackish  discol- 
oration, and  hairs  from  one-eighth  to  one-fourth  of  an  inch  could 
be  readily  removed  and  floated  in  water  or  alcohol.  In  some 
cases  there  was  mere  discoloration  without  an  associated  hairy 
growth,  as  reported  by  Gottheil,  Stokes,  Ciaglinski  and  Hewelke 
and  Sendziak.  This  discoloration  was  soft,  mushy  in  character, 
and  could  be  freely  but  somewhat  incompletely  removed  by  light 
scraping.  The  cases  occurred  for  the  most  part  in  early  syphi- 
litics,  and  were  observed  in  the  process  of  the  examination  of 
the  tongue  for  the  presence  or  absence  of  mucous  plaques,  or 
the  coated  or  non-coated  state  of  the  tongue  in  non-syphilitics. 
All  of  the  cases  occurred  in  males.  Most,  but  not  all,  of  the  S3^ph- 
ilitics  were  using  at  the  time  astringent  and  antiseptic  mouth  lo- 
tions. The  patches  disappeared,  however,  in  some  of  the  cases, 
in  spite  of  the  persistent  use  of  the  astringent  antiseptic  mouth 
lotions. 

One  patient,  affected  with  gonorrhea  but  not  with  syphilis, 
was  taking  sandalwood  oil  internally,  but  the  patch  persisted  for 
some  time  after  the  internal  administration  of  the  oil  was  with- 
drawn.    It  disappeared  entirely  after  a  lapse  of  several  months. 

In  two  cases  syphilitic  infection  was  of  long  standing;  one 
patient  had  an  extensive  leukoplakia  of  the  tongue,  and  these 
areas  were  free  from  the  yellowish-brown  discoloration,  which 
occupied  an  irregularly  oval  area  near  the  center,  anterior  to  the 
circumvallate  papillae.  Most,  but  not  all,  of  the  cases  occurred 
in  patients  who  used  tobacco  immoderately.  Dietary  indiscre- 
tions and  gastrointestinal  disturbances  were  in  evidence  in  the 
majority,  but  not  in  all  of  the  cases.  The  patches  were  evanes- 
cent and  transient  in  all  the  cases,  fading  or  disappearing  with- 
out treatment  or  attention,  and  occasionally  relapsing  from  un- 
toward local  or  general  influences.  These  cases  lacked  the  clean- 
cut  clinical  characteristic's  of  the  first  two  well-defined  cases,  in 
which  the  color  was  more  intense,  the  hairs  longer,  more  numer- 
ous and  interwoven,  the  patches  thicker,  more  fur-like  and 
sharply  defined,  and  more  persistent  and  stable  in  character.     I 


/ 


Fi :;.  4. — The   same   napilla-like  bodies  cut   transversely  and   imparting  tlu 
appearance  of  epithelial  nests  clustered  in  circles. 


Fi!'..  5. — Su|)erricial  urisjin  tit   the  iiair-like  rdament> 


H  E  I  D  I  N  G  S  F  E  [.  D  169 

am  inclined  to  believe  that  several  of  the  cases  reported  in  the 
literature  belong  to  this  second  class  of — if  I  may  be  pardoned 
the  term — spurious  or  pseudo  cases. 

Microscopic  Examination. —  The  microscopic  appearance  of 
the  hairy-like  filaments  was  fairly  constant,  when  compared  with 
each  other  and  with  those  described  in  the  literature.  Specimens 
from  the  pseudo  or  spurious  cases  could  not  be  diflferentiated 
microscopically,  except  for  length  and  thickness,  from  those  of 
the  two  well-defined  ones.  Specimens  unstained  and  stained  bv 
various  methods  were  examined ;  the  unstained  specimens  for 
the  most  part  showed  a  more  regular  and  better  preserved  outline. 
The  color  of  the  unstained  specimens  is  a  diffuse  yellowish- 
brown,  as  already  noted  by  Schech,  Mourek  and  others. 

The  outline  is  an  elongated  cylinder,  hair-like  in  general  ap- 
pearance. The  resemblance  to  a  hair  is  accentuated  in  many  in- 
stances by  the  presence  of  a  zone  analogous  to  the  medullary 
canal.  In  many  there  are  several  of  these  zones  of  varying  color 
intensity,  and  on  close  examination  they  are  found  to  owe  their 
presence  to  the  fact  that  a  single  filament  is  often  composed  of 
two  or  more  closely  united  shafts.  These  shafts  are  united  the 
greater  part  of  their  entire  length ;  they  become  separate  and 
distinct  from  each  other  a  short  distance  from  the  distal  extrem- 
ity, imparting  a  peculiar  tuft-like  appearance,  not  altogether  un- 
like that  observed  in  a  pineapple  (Fig.  1,  A).  Occasionally  one  of 
the  united  shafts  will  become  dissociated  at  some  more  median 
point,  and  impart  an  appearance  not  altogether  unlike  that  of  the 
leaf  to  a  stalk  of  Indian  corn  (Fig.  1,  D).  The  resemblance  to 
Indian  corn  becomes  more  marked  if  there  are  several  lateral  dis- 
sociations. 

Lateral  deviations  have  been  noticed  by  S^^hech  and  other 
early  observers.  On  closer  examination  under  higher  magnifi- 
cation, the  filaments  are  observed  to  be  composed  of  thin,  non- 
nucleated,  stratified  closely  su'^erimposed  epithelial  cells.  Their 
cornified,  non-nucleated  character  can  be  confirmed  if  the  fila- 
ments are  macerated  with  gentle  heat  in  a  solution  of  potassium 
h^^droxid.  The  individual  cells  are  superimposed  in  such  a  way 
as  to  produce  serrated  borders ;  the  serrations  are  constantly  di- 
rected downward,  producing  a  peculiar  tesselated  eflfect.  which 
can  be  compared  to  the  scales  on  the  surface  of  a  pineapple.  This 
imbricated  character  has  been  frequently  noted  in  the  literature; 
it  is  not  marked  enough  to  conjure  up  the  resemblance  of  a  row 
of  inverted  funnels,  as  described  by  Brosin,  nor  is  their  order,  as 
he  states,  ever  reversed,  so  that  they  partake  of  the  appearance 
of  a  harpoon  or  trident.     For  similar  reasons,  the  spike-like  ap- 


170  DAN  BRIDGE    MEMORIAL 

pearance  or  resemblance  to  the  head  of  a  wheat-stalk,  described 
by  Mourek,  is  not  to  be  discerned ;  surface  indentations  were  not 
observed  to  recall  the  "corncob"  effect  describe!  by  Levisseur. 
The  serrations  at  the  border  are  directed  toward  the  base,  and 
away  from  the  rounded  and  cleft  extremities,  constantly  enough 
to  permit  a  ready  differentiation  of  the  distal  from  the  proximal 
■extremity. 

In  well-stained  specimens  the  filaments  were  observed  under 
oil-immersion  to  be  thickly  studded  wdth  masses  of  cocci,  which 
morphologically  resembled  the  common  pus  germs.  They  were 
present  in  exceedino-ly  large  numbers,  were  intracellular  and  ex- 
tracellular, and  often  in  such  density  as  to  resemble  pure  cul- 
tures of  the  common  staphylococci.  Larger  and  more  deeply 
stained  cocci  and  diplococci  were  interspersed  here  and  there 
together  with  bacilli,  leptothrix,  and  various  forms  of  organisms 
commonly  found  in  the  mouth.  In  addition  to  the  various  stained 
micro-organisms,  a  few  large,  round,  highly  refractive,  double- 
contoured  bodies,  some  larger,  some  smaller,  often  in  such  prox- 
imity as  to  impart  a  budding  character,  were  observed  here  and 
there  in  most  of  the  specimens  examined.  They  were  not  numer- 
ous enough  to  assume  pathogenic  importance,  and  to  all  appear- 
ances their  presence  partook  of  a  coincidental  character.  Some 
unrecognizable  fungi  and  micro-organisms  were  also  observed ; 
the  micrococci,  however,  predominated  greatly  over  all  other 
forms. 

Culture  Exf>criuients. — Culture  experiments  were  attempted 
in  both  genuine  and  spurious  cases.  The  affected  surfaces  were 
carefully  sponged  with  ether  and  a  5  per  cent,  glucose  agar;  nu- 
trient agar  and  blood-serum  were  carefully  inoculated  with  re- 
moved filaments  and  nlatinum  loon  inoculations  from  the  affected 
area.  Some  of  the  cultures  were  kept  at  38°  C,  others  at  room 
temperature. 

The  cultures  uniformly  remained  sterile  or  became  the  seat 
of  innumerable,  small,  glistening,  white,  superficial  colonies,  which 
morphologically  and  microscopically  resembled  in  every  particu- 
lar Staphylococcus  albus.  No  fungus  was  evident  even  on  pro- 
longed standing  in  any  of  the  cultures  examined. 

Histology. — A  biopsy  was  obtained  only  in  Case  I,  and  the 
histologic  report  with  accompanying  illustrations  is  the  first,  to 
my  knowledge,  to  he  recorded  for  the  affection.  Under  low 
power,  the  filaments  when  cut  vertically  and  longitudinally  to 
their  long  axis,  are  observed  to  reach  upward  and  forward  in  ir- 
regular parallels  (Fig.  2).  Many  of  the  intertwined  filaments  are 
cut  transversely  and  obliquely.  The  filaments  preserve  for  them- 
selves a  feather-like  appearance.  When  cut  transversely  to  their 
long  axis  their  continuity  is  preserved  only  a  short  distance,  and 


¥u..  6. — Blood  cavity  strongly  magnified,  showing  its  intra-epithelial  posi- 
tion.    Cavity  is  lined  with  a  layer  of  endothelial  cells. 


Fk;. 


'. — Small  1)lood  cavity  within   ilu    cin.irrmis  witli  areas  of  edematous 
and   degeneratetl   epithelial   cells   at   the   rete   papillary   border. 


HEIDI  NGSFELD  171 

most  of  them  appear  as  small,  round  or  oblique  fragments.  The 
filaments  can  often  be  directly  traced  to  their  origin  from  papilla- 
like projections  of  the  stratum  corneum.  The  stratum  corneum 
elongations  promptly  take  on  a  fringe  of  serrated,  more  loosely 
arranged  and  deeper  staining  cells;  ihey  often  coalesce  within  a 
short  distance  of  their  proximal  extremities  with  one  or  more 
adjacent  filaments,  to  form  double,  triple  or  quadruple  filaments. 
Acanthosis  is  another,  marked  pathologic  feature.  The  rete  and 
the  papillae  are  considerably  hypertrophied,  and  there  is  a  very 
extensive  downward  prolongation  of  almost  every  fourth,  fifth 
or  sixth  interpapillary  process  of  the  rete  ^Nlalpighi.  The  lower 
layer  of  columnar  cells  is  sharply  defined,  well  preserved  and  in 
a  state  of  active  proliferation.  The  pars  papillaris  and  subjacent 
tissue  are  entirely  devoid  of  any  marked  pathologic  change  save 
a  diftused,  mild  infiltration  of  inflammatory  products,  tlie  dis- 
tribution of  which  is  limited  almost  exclusively  to  the  pars  pap- 
illaris. 

One  of  the  most  striking  pathologic  changes,  and  possibly 
second  in  importance  only  to  the  fidaments,  is  the  formation  of 
papilla-like  bodies  within  the  rete  Malpighii  (Fig.  3).  They  are 
differentiated  from  the  rete,  in  Vv'hich  they  are  situated,  by  a  well- 
defined  layer  of  more  deeply  stained  columnar  basal  ceils.  Their 
well-defined  interpapillar}'  spaces  are  devoid  of  fibro-connective 
tissue  and  filled  with  epithelial  cells  of  the  rete.  They  are  ftir- 
ther  differentiated  from  normal  papilhe  by  their  diminutive  type. 
If  cut  obliquely  or  on  cross  section,  they  partake  of  the  appear- 
ance of  epithelial  nests  (Fig.  4),  and  it  is  not  unusual  to  note 
six  to  twelve  or  more  of  such  nests  clustered  in  a  circle.  If  cut 
longitudinally  thev  can  be  traced  directly  to  the  surface  to  points 
where  the  filaments  take  their  origin  (Fig.  5).  Having  assumed 
that  these  intra-epitheliuni  placed  papillae  are  the  origin  of  the 
hairs,  I  have  termed  them  "epithelial  founts." 

The  stratum  corneum  is  more  or  less  imperfectly  preserved. 
In  some  pLices  it  is  of  normal  thickness,  structure  and  staining 
properties,  and  covers  a  fair  extent  of  surface.  In  places  it  is 
almost  entirely  lacking,  and,  when  present,  rises  perpendicularly 
from  the  surface  to  form  the  proximal  extremities  of  the  hair- 
like filaments.  Where  it  is  preserved,  it  is  often  covered  or  par- 
tially covered  with  a  thick  layer  of  partially  stratified,  nucleated 
epithelial  cells.  Groups  of  degenerated  cells  are  occasionally  ob- 
served at  the  tips  of  the  papillae  or  in  the  epidermis  near  the  pap- 
illary border  (Fig.  6).  These  cells  are  often  surrounded  by  a 
single  layer  of  endothelial  cells ;  their  yellowish  color,  small  ho- 
mogeneous appearance,  angular  otitline,  with  interspersed  darkly- 
stained  lymphocytes,  indicate  that  they  are  blood  accumulation^. 


172  DAN  BRIDGE    MEMORIAL 

Inasmuch  as  such  accumulations  have  been  observed  and  recorded 
in  the  corneous  substance  of  cutaneous  horns  by  Joseph  and 
others,  the  analogy  is  plausible.  These  "blood-cavities"  and  the 
rete-papillary  border  occasionally  contain  large  rounded,  hyaline 
or  faintly  granular  double  culture  bodies,  which  are  apparently 
cell  degenerations  rather  than  pathogenic  spores,  although  they 
bear  a  morphologic  resemblance  to  spores  to  which  pathogenic 
importance  has  been  attributed  (Fig.  7).  They  are  often  em- 
bedded in  a  mass  of  large,  edematous  vacuolated  cells  situated 
at  the  papillary  border  of  the  epidermis,  which  resemble  the  de- 
generative cell  changes  in  Paget's  disease. 

The  pathology  cannot  be  dismissed  without  a  brief  compara- 
tive reference  to  cutaneous  horns,  ichthyosis  hystrix,  leptothrix 
and  hair.  The  histopathologic  similarity  which  some  of  these 
affections  bear  to  hairy  tongue  is  remarkable  to  the  degree  with 
which  their  clinical  characteristics  are  dissimilar;  and  vice  versa, 
the  affections  which  preserve  the  greatest  degree  of  clinical  re- 
semblance show  the  least  histopathologic  resemblance.  Cutane- 
ous horns,  which  have  little  or  nothing  in  common  with  hairy 
tongue,  have  much  in  common  pathologically.  They  are  com- 
posed of  masses  of  cornified,  or  at  least  partially  stratified,  epi- 
thelial cells,  arranged  with  wonderful  cohesion  into  dense  elon- 
gated columns,  row  after  row,  separated  by  valley-like  clefts  re- 
sembling the  medullated  canals  of  hair.  Intra-epithelial  spaces 
containing  blood  are  also  observed.  The  origin  is  purely  epi- 
dermal, and  the  base  rests  on  and  is  apparently  developed  from 
intra-epithelially  placed  papillae  and  interpapillary  processes  rest- 
ing above  the  area  of  the  true  papillae,  and  true  interpapillary 
processes,  unless  the  latter  have  disappeared  from  pressure  atro- 
phy. The  former  papillae  and  interpapillary  processes  corre- 
spond to  the  intra-epithelially  placed  "epithelial  founts"  of  hairy 
tongue. 

Ichthyosis  hystrix,  which  preserves  possibly  more  clinical  than 
histopathologic  resemblance  to  hairy  tongue,  preserves  little  his- 
tologic similarity  except  a  marked  hyperkeratosis.  The  hyper- 
keratosis, however,  is  arranged  parallel  rather  than  perpendicular 
to  the  surface,  and  the  spinous  processes  are  the  result  of  kera- 
totic  accumulations  spread  irregularly  over  the  surface  of  four 
or  five  hypertrophied  papillae.    The  inflammatory  exudate  is  more 


H  E  1  D  I  N  G  S  F  E  L  D  173 

perivascular,  less  diffused  in  character  and  more  circumscribed  to 
the  capillary  vessels  of  the  pars  papillaris. 

Leptothrix,  which  has  little  or  .nothing  clinically  in  common 
with  hairy  tongue,  shows  a  striking  resemblance  under  the  mi- 
croscope, in  that  the  affected  hairs  are  coated  with  an  accumu- 
lation of  loosely  adherent  cells  and  detritus  containing  myriads 
of  micrococci  and  other  micro-organisms.  The  morphologic  resem- 
blance, under  the  microscope,  of  hair  affected  with  leptothrix  to 
the  filaments  of  hairy  tongue  is  very  striking.  An  additional  point 
of  resemblance  is  the  discoloration,  which  in  leptothrix  is  often 
yellow  or  red,  and  in  hairy  tongue  black  to  brownish-yellow, 
Pathogenically  there  can  be  little  in  common  in  the  two  aff'ec- 
tions.  The  gross  clinical  resemblance  which  filaments  bear  to  hair 
is  striking  enough  and  gives  the  affection  a  misnomer.  Remark- 
able in  many  of  its  microscopic  features,  the  resemblance  is  micro- 
scopically and  histopathogenically  a  paradox  that  requires  no 
comment.  In  origin,  development,  essentials  of  structure  and 
pathogenesis  they  naturally  share  nothing  in  common  with  hair. 

GENERAL    DEDUCTIONS. 

Hairy  tongue  can  be  conveniently  divided  into  two  general 
classes :  ( 1 )  True,  idiopathic,  or  genuine  cases,  characterized  by 
well-defined  stable,  black-brown  or  yellow-brown,  thick,  soft,  fur- 
like patches  covered  with  densely  intertwined  hair-like  filaments, 
easily  measuring  from  one-fourth  to  one-half  inch  in  length;  and 
(2)  false,  pseudo  or  spurious  cases,  characterized  by  thickish,  yel- 
low-brown or  greenish  discolorations,  of  unstable,  evanescent 
character,  covered  with  a  soft  mushy  detritus,  occasionally  con- 
taining short  filaments  measuring  one-eighth  to  one-fourth  of  an 
inch  in  length.  The  true  cases  owe  their  origin  to  some  anomaly 
of  development,  probably  of  congenital  nature,  in  the  sense  that 
the  germinal  products  from  which  they  are  developed  are  pres- 
ent from  birth,  but  do  not  undergo  growth  and  developmental 
changes  until  early  adolescence  or  some  later  period  in  life.  Such 
an  origin  is  assumed  and  very  generally  conceded  for  moles,  vas- 
cular, pigmented  papillomatous  and  unilateral  nevi,  cutaneous 
homs,^®  etc.,  and  can  be  extended  with  equal  propriety  to  this 
affection,  all  the  more  since  the  histopathology  reveals  an  anom- 


174  DAN  BRIDGE    MEMORIAL 

aly  of  development  (whose  striking  similarity  to  cutaneous  horns 
has  already  been  alluded  to)  rather  than  any  evidence  of  an  in- 
fectious or  inflammatory  nature.  An  anomalous  development 
and  congenital  origin  is  further  evidenced  by  the  fact  that  the 
true,  idiopathic  or  genuine  cases  are  of  stable  character,  and  re- 
main unchanged  in  size  and  form  for  indefinite  periods,  and  are 
localized  to  definite  areas.  Such  would  not  likely  be  the  case  if 
they  were  of  infectious  origin  or  inflammatory  character  result- 
ing from  local  or  general  causes. 

The  pseudo  or  spurious  cases  are  unstable  and  evanescent, 
and  probably  owe  their  origin  to  such  local  or  general  irritating 
and  infectious  causes  as  tobacco,  antiseptics,  astringents,  syphi- 
lis, etc.  The  presence  of  the  filaments  is  probably  due  to  an  in- 
flammatory hypertrophy  of  the  papillae  fiii formes.  These  cases 
in  varying  degrees  of  intensity  can  be  frequently  noted,  partic- 
ularly in  the  early  stages  of  syphilis,  and  constitute  no  uncom- 
mon affection.  The  diagnosis  can  be  easily  confirmed  by  remov- 
ing some  of  the  grumous  coating  of  the  discolored  tongues  by 
means  of  fine  forceps,  and  floating  it  in  clear  water  or  alcohol. 
The  hair-like  filaments  can  then  be  readily  seen  with  the  naked 
eye.  The  majority  of  cases  recorded  in  literature  probably  be- 
long to  this  group.  A  parasitic  origin  for  the  affection  could  not 
be  established  either  on  clinical,  histopathologic  or  bacteriologic 
grounds ;  it  does  not  develop  or  spread  clinically  like  a  parasitic 
affection.  Inoculation  experiments  were  negative  in  the  sense 
that  the  affections  could  not  be  distributed  to  other  unaffected 
parts  of  the  tongue.  It  failed  to  spread  to  the  abrasions  and  ex- 
coriations of  an  intercurrent  cancer  of  the  tongue.  The  histo- 
pathology  reveals  chiefly  anomalous  structural  changes,  and  the 
absence  of  the  marked  inflammatory  changes  generally  incident 
to  chronic  and  acute  infectious  and  localized  irritations.  The 
fundamental  abnormality  is  the  presence  of  abnormal  papillae  and 
interpapillary  pro'^esses  or  "filament  founts"  situated  within  the 
epidermis,  from  which  the  abnormally  elongated,  stratified  and 
keratosed  filaments  trace  their  direct  origin.  Some  of  the  basal 
'"ells  at  the  papillary-rete  border  showed  vacuolated  and  edema- 
tous change,  to  which,  however,  no  especial  significance  could  be 
attributed.    The  filaments  were  freely  studded  with  micro-organ- 


H  E  I  D  I  N  G  S  F  E  L  D  175 

isms  which  resembled  Staphylococcus  albus  morphologically,  to 
which  likewise  no  special  significance  could  be  attached.  A  few 
double-contoured  bodies  were  occasionally  observed  among  the 
filaments  and  in  the  deeper  structures,  to  which  no  important  sig- 
nificance was  attributed.  The  bacteriologic  findings  were,  as 
already  stated,  sufficiently  negative  in  character  to  preclude,  in 
my  opinion,  a  parasiti"  etiology  for  the  aflfection. 

REFERENXES. 

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Zunge.     Zeitschrift  f.  klin.  Med..  1893,  xxii,  626. 

25  Sendziak:   Beitrag  zur  Etiologie  der  sogenannten  Schwarzen-Zunge. 
Moiiatslieft  f.  OJirenheilkunde,  1894,  xxviii,  112. 

26  Rostowjew:  Hospitalz.  Botkin,   1896.  No.  8. 

27  Gottheil:  Arch.  f.  Pediat.,  1889,  p.  255. 

28  Lucet:  Arch,  de  Parasitol,  Mav  20,  1901. 

29  Gastou   and   Laselet :   Tr.   de   Soc.   Franc,   de   Dermat.   et   de   Syph., 
March  18.  1909,  xx.  No.  5. 

30  Gueguen  :  Arch,  de  Parasitol,  1909,  xii.  No.  8. 

31  Levissenr:  Ne^o  York  State  Med.  Journal,  1899,  xlix,  42. 


176  DANDRIDGE    MEMORIAL 

32  Schnabel :  Haar-Zunge,  Inaug.  Dissert.,  Leipzig,  1904. 

33  Schourp :  Monatschr.  f.  Harnkr.  u.  sex.  Hyg.,  in,  No.  2. 

34  Audry  and  Dalous:  Jour,  de  mal.  cutan.,  1904,  xvi,  801. 

35  Hallopeau:  Ann  de  Dermaf.  et  de  Syph.,  1896,  series  3,  vn,  744. 

36  Mourek:  Arch.  f.  Dermat.  u.  Syph.,  1894,  xxix,  369. 

37  Vollmer:  Arch.  f.  Dermat.  u.  Syph.,  1898,  xlvi,  13. 

38  Philip :  Momtsh.  f.  prakt.  Dermat.,  1904,  xxxix,  630. 


HAND  INFECTION  APPARENTLY  DUE  TO  BACILLUS 

FUSIFORMIS.* 


BY    WILLIAM    H.    PETERS. 


While  the  actual  role  of  Bacillus  fusiformis  in  the  production 
of  lesions  in  the  human  body  is  still  suhjudice,  we  cannot  fail 
to  recognize  its  importance  as  a  factor,  if  we  glance  at  the  in- 
creased number  of  pathologic  lesions  from  which  it  has  been  iso- 
lated. The  organism  has  been  observed  in  ulcero-membranous 
angina,  hospital  gangrene,  noma,  appendicitis,  diphtheria,  fetid 
bronchitis,  gangrenous  laryngitis,  pyorrhea  alveolaris,  brain  ab- 
scess and  in  the  healthy  mouth. 

According  to  Jungano  and  Distaso,^  Plant  first  described  it  in 
1894  in  a  case  of  ulcerous  angina,  while  Veillon  and  Zuber  were 
probably  the  first  to  isolate  the  bacillus  in  pure  culture.  Vin- 
cent's descriptions  appeared  about  two  years  after  Plant's.  The 
organism  has  been  grown  in  pure  culture  by  Ellerman,  Weaver,- 
Tunnicliff,^  Leucowitz,  Leiner,  Repaci,  and  Ghon  and  Mucha. 

Five  cases  of  unusual  infection  with  fusiform  bacilli  and  spi- 
rochsetes  have  been  studied  by  me. 

Case  I. — S.  F.,  male  aged  four,  was  admitted  to  the  Cincin- 
nati Hospital  October  5,  1909.  He  had  a  typical  lobar  pneumo- 
nia with  delayed  resolution,  which  was  followed  by  an  abscess  of 
the  lung.  Death  ensued  sixteen  days  after  admission.  Smear 
preparations  of  the  pus  obtained  before  death  from  the  thorax, 
by  aspiration,  revealed  fusiform  bacilli  and  spirochsetes  in  great 
numbers  and  streptococci.  The  fusiform  bacilli  measured  from 
2.7 /x  to  7.0 /i.  by  0.5 /x.  Apparently  two  varieties  of  spirochgetes 
were  observed ;  thick  ones  with  irregular,  loose  windings,  corre- 
sponding to  the  refringens  type,  and  others  composed  of  two 
or  three  turns  and  of  regular  amplitude.  The  same  organisms 
were  found  in  the  sputum,  together  with  a  third  type  of  spiro- 
chaete,  viz.,  dentium. 

*  Reprinted  from  The  Journal  of  Infectious  Diseases,  vol.  viii,  No.  4. 
June,  1911,  pp.  455-462. 

177 


178  DAN  BRIDGE    MEMORIAL 

Case  II. — P.  S.,  a  white  male,  aged  forty-five,  was  admitted  to 
the  Cincinnati  Hospital  October  3,  1910,  with  marked  dyspnea, 
laryngeal  stridor  and  an  irregular  pulse.  He  died  one  hour 
after  admission.  Post-mortem  examination  revealed  a  syphilitic 
ulceration  and  edema  of  the  larynx  and  trachea  and  other  ter- 
tiary lesions.  Cover-slip  preparations  were  made  from  the  ulcer 
at  the  base  of  the  larynx,  demonstrating  fusiform  bacilli  resem- 
bling those  described  by  \^incent,  and  spirochsetes  of  the  refrin- 
gens  type. 

Case  III. — F.  S..  the  patient,  had  a  chronic  fetid  bronchitis. 
Smear  preparations  of  the  purulent  secretions  showed  the  pres- 
ence of  Bacillus  fusifonms  in  great  numbers  and  an  absence  of 
spirochsetes. 

These  cases  are  mentioned  briefly  with  a  twofold  purpose, 
viz.,  demonstration  of  the  organism  in  question  and  its  relative 
significance  when  associated  with  respiratory  disorders. 

Case  IV. — J.  K.,  aged  thirty-eight,  laborer.  On  March  17, 
1911,  at  Gadsden,  Ala.,  he  struck  a  man  in  the  teeth,  injuring  the 
index  and  middle  fingers  of  the  right  hand.  Intense  swelling, 
edema  and  a  foul  discharge  characterized  the  condition.  Smear 
preparations  made  from  the  discharge  on  April  9  showed  the 
presence  of  fusiform  bacilli  and  streptococci.  Xo  spirochaetes 
demonstrable. 

Before  proceeding  with  the  case  that  was  studied  culturally 
as  w^ell  as  microscopically,  I  should  like  to  refer  to  the  case  re- 
ported by  Hultgens,*  a  seven-year-old  girl  who  showed  partial 
gangrene  of  the  left  index  finger.  In  smear  preparations  he 
found  fusiform  bacilli  and  spirochaetes.  He  doe^  not  describe 
the  spirochgetes,  but  calls  them  Spirochcota  denticola.  His  patient 
had  carious  teeth  and  had  been  in  the  habit  of  biting  her  finger- 
nails. Film  preparations  made  from  her  carious  teeth  showed 
the  presence  of  these  same  organisms.  Apparently  no  cultural 
studies  were  attempted.  The  source  of  infection  makes  this  and 
the  following  case  interesting,  especially  in  view  of  the  fact  that 
no  cases  are  reported  of  direct  transmission  from  one  individual 
to  another. 

Case  \^. — A.  W..  aged  thirty-four,  bartender  by  occupation. 
On  September  6,  1910,  he  struck  a  man  in  the  teeth,  injuring  the 
base  of  the  little  finger  of  his  left  hand.  Two  days  later  the  fin- 
ger was  swollen  and  discharging  a  foul  pus.  He  was  admitted  to 
the  Cincinnati  Hospital,  with  a  temperature  of  99.8°,  pulse  and 


w 


'I 


♦ 


'V 


(■•<->' 


% 


Fic.    1. — Film   preparation    from    infected   hand.    Case   5.   deniunstrating   B. 
fiisifortuis.  XFOOO.     Stained   with  carhnl-fuchsin. 


Fk;.   2. — Smear   from   infected   hand.   Case   5,   demonstrating   spirochaetes. 
Xl.OOi).  Staired  with  polychrome  methylene  blue  for  twenty-four  hours. 


PETERS  179 

respiration  normal.  Two  free  incisions  were  made,  and  the  hand 
immersed  in  a  continuous  bichloride  bath.  Nine  days  after  in- 
jury the  wound  was  not  doing  well ;  had  a  chronic  persistent  ap- 
pearance and  was  still  discharging.  Eighteen  days  following  in- 
jury the  left  hand  and  forearm  were  swollen  and  markedly  edem- 
atous, and  the  discoloration  assumed  a  purplish  hue.  The  wounds 
were  ragged,  irregular,  and  surrounded  by  cauliflower-like  ex- 
crescences, with  evidence  of  deep  destruction  of  the  tissues.  The 
appearance  of  these  wounds  was  suggestive  of  epithelioma.  The 
patient  was  unwilling  to  submit  to  further  surgical  interference 
and  was  discharged.  He  made  a  slow  recovery,  as  was  learned 
later,  and  was  well  fifty-four  days  after  the  injury. 

Smear  preparations  from  the  Vv-ound.  made  September  20, 
showed  numerous  leukocytes  and  almost  pure  culture  of  fusi- 
form bacilli  and  spirochsetes.  The  bacilli  for  the  most  part  are 
long  and  regular,  with  pointed  ends,  and  thicker  in  the  middle. 
They  lie  side  by  side,  between  the  cells,  or  end-to-end.  and  some- 
times in  irregular  clumps.  In  size  the  bacilli  vary  from  2.7  ju,  to 
8.1  /t  in  length  by  0.6  fi  in  breadth.  Ihe  spiroch?etes  are  very  nu- 
merous, and  at  least  two  types  are  visible.  Most  of  them  show 
three  or  four  turns  which  are  of  irregular  amplitude,  correspond- 
ing to  the  refringens  type.  Their  extremities  are  parallel  to  the 
long  axis  of  the  spiroch?ete.  with  two  or  three  thick  regular  turns 
corresponding  to  Spirochceta  recta,  and  another,  with  four  or  five 
regular  turns,  but  which  are  much  thinner,  corresponds  to  Spiro- 
clicrta  tmuis.^  The  spirochsetes  measure  from  9.0  ju  to  16.2 /i  in 
length  by  less  than  0.4  ix  in  breadth  ( Spencer  apochromatic  2  mm. 
ocular  No.  8).  Smear  preparations  forty-six  days  after  the  in- 
jury showed  the  same  organisms.  A  mixed  infection  was  evi- 
denced by  the  presence  of  a  limited  number  of  cocci  and  small 
bacilli.  The  spirochsetes  were  not  so  abundant,  appeared  thinner 
than  when  first  observed,  and  did  not  stain  so  well. 

Slants  of  Dorset's  egg  medium  were  inoculated  with  the  pur- 
ulent secretion  taken  from  this  case  of  hand  infection.  After  an- 
aerobic incubation  at  2)7°  C.  for  three  days,  colonies  of  two 
kinds  appeared,  cocci  and  fusiform  bacilli.  By  transplanting 
from  the  small  colonies  of  spindle-shaped  bacilli,  pure  cultures 
were  obtained. 

Morphology  and  Staining  Reactions. — In  smear  preparations 
from  twenty-four-hour  cultures,  the  fusiform  bacilli  are  delicate 
pointed  rods  and  usually  straight.  As  they  mature  they  become 
long,  slender  rods  with  pointed  ends,  and  somewhat  thicker  in 
the  middle.  Verj^  frequently  they  are  slightly  curved.  They 
measure  4.5  fi  to  46.8  /u,  in  length  by  0.6  fx  in  breadth. 


180  DANDRIDGE    MEMORIAL 

In  some  of  the  cultures  wavy  forms  may  be  observed.  The 
morphologic  characteristics  of  these  are  not  unlike  those  of  the 
bacilli.  The  protoplasm  reacts  to  aniline  dyes  and  to  light  in  the 
same  way;  and  the  presence  of  metachromatic  granules  is  sug- 
gestive of  fusiformis.  The  longer  bacilli  most  frequently  con- 
tain four  or  more  metachromatic  granules,  while  the  shorter 
forms  contain  two.  In  old  cultures  the  granules  are  stained  less 
intensely  or  may  be  entirely  absent.  Suspended  in  Gram's  iodine 
solution,  they  do  not  give  the  starch  reaction. 

In  making  film  preparations  fro^m  solid  cultures,  the  bacilli 
often  remain  adherent  throughout  their  length,  forming  bundles. 
Occasionally  two  bacilli  may  be  seen  lying  side  by  side,  so  close 
together  as  to  make  one  think  that  they  divide  longitudinally; 
however,  there  are  no  indications  of  terminal  splitting.  Some 
appear  only  half  as  thick  as  others.  On  the  other  hand,  there  is 
evidence  in  the  film  preparations  that  transverse  division  occurs. 
Some  of  the  bacilli  seem  to  be  constricted,  and  here  the  proto- 
plasm is  thinner  and  less  granular.  The  fusiform  bacilli  as  well 
as  the  spirochaetes  are  stained  by  Loeffler's  methylene  blue,  poly- 
chrome methylene  blue,  carbol  gentian  violet,  carbol  fuchsin,  and 
and  by  the  Giemsa  and  Romanowski  stains.  Carbol  fuchsin  and 
polychrome  meth)dene  blue  are  the  most  satisfactory.  Specimens 
were  stained  in  polychrome  methylene  blue  for  twenty- four  hours, 
washed  with  water  and  mounted  in  balsam.  The  spirochaetes 
stain  less  intensely  than  the  bacilli. 

The  definition  of  B.  fusiformis  is  beautifully  demonstrated 
by  the  aniline  black  method.  Neither  the  bacilli  nor  the  spiro- 
chsetes  retained  the  stain  in  Gram's  method,  contrary  to  the  state- 
ment of  Jungano  and  Distaso. 

Cultural  Properties. — The  cultures  were  grown  anaerobically 
by  the  pyrogallic  acid  method.  The  colonies,  not  unlike  streptococ- 
cus colonies,  are  small  and  delicate,  with  slightly  raised  centers 
about  1  or  2  mm.  in  diameter.  The  best  growth  was  obtained  at 
37°  C.  In  the  hanging  drop  the  organisms  show  no  active  or 
progressive  motility,  but  considerable  vibratory  motion,  espe- 
cially at  one  end. 

So  far  as  the  viability  of  Bacillus  fusiformis  on  artificial 
media  is  concerned,  TunnicliflF  found  them  alive  fifty-five  days 


Fig.  3.— Pure  culture  of  B.  fusifoniiis.  Xl.lXMI.     Stained  with  polychrome 
methylene  hlue  for  forty-eight  hours. 


^ 


\ 


Fk;.  4. — Pure  culture  of  B.  fusifoniiis.  Xl.CGO.     Stained  with  polychrome 
methylene  blue  for  forty-eight  hours,  showing  wavy  forms. 


PETERS  181 

after  inoculation.  Cultures  on  Dorset's  egg  medium  and  Loeff- 
ler's  blood  serum  have  been  found  by  myself  viable  twenty,  forty 
and  forty-seven  days  after  transplanting.  The  viability  of  the 
culture  is  conserved  for  some  time  in  the  refrigerator  or  main- 
tained by  frequent  transfers.  Twenty  subcultures  made  during 
the  past  seven  months  have  been  grown  successfully. 

Loeffler's  blood  serum  and  Dorset's  egg  medium  are  produc- 
tive of  the  most  luxuriant  growth,  the  colonies  appearing  as  deli- 
cate irregular  white  masses  with  slightly  raised  centers.  Growth 
is  scarcely  visible  at  the  end  of  twenty-four  hours,  but  after 
forty-eight  or  seventy-two  hours'  incubation  the  colonies  measure 
1  or  2  mm.  in  diameter.  A  flocculent  growth  is  usually  observed 
in  the  water  of  condensation.  Ascites  broth  offers  a  very  favor- 
able means  of  cultivation.  The  growth  is  heavy,  luxuriant,  floc- 
culent, and  sinks  to  the  bottom.  By  agitating  the  tubes  this  may 
be  divided  into  small  particles.  On  rabbit's  blood  agar  luxuriant 
growth  was  obtained,  resembling  that  seen  on  Loeffler's  blood 
serum.  When  such  a  culture  was  placed  under  aerobic  condi- 
tions, the  culture  medium  darkened  and  was  black  a  week  later. 
In  Dunham's  peptone  solution  there  was  a  slight  flocculent  growth 
which  settled  on  the  bottom.  In  litmus  milk  limited  growth  oc- 
curred after  seventy-two  hours  at  37°,  but  no  coagulation  took 
place.  When  broth  with  a  reaction  of  1  per  cent,  acid  to  phenol- 
phthalein  and  containing  1  per  cent,  of  dextrose,  lactose,  sacchar- 
ose, maltose  or  mannite  was  inoculated,  no  growth  occurred,  but 
the  addition  of  0.5  c.c.  of  defibrinated  rabbit's  blood  to  6  c.c.  of 
these  various  sugar  broths  yielded  luxuriant  growths.  Arid  pro- 
duction was  marked  at  the  end  of  seventy-two  hours,  excepting 
in  saccharose.  The  litmus  in  dextrose  and  lactose  broths  was 
entirely  reduced.  The  same  luxuriant  growth  was  obtained  in 
litmus  milk  when  0.5  c.c.  of  defibrinated  rabbit's  blood  was  added. 
No  growth  appeared  upon  -(-1  agar  or  upon  1  per  cent,  glucose 
agar. 

When  the  stoppers  were  removed  from  the  culture  tubes  a 
foul  odor  was  given  off'  suggestive  of  skatol.  The  reaction  for 
indol  with  potassium  nitrite  and  sulphuric  acid  was  negative. 

Resistance. — As  far  as  I  know,  the  resistance  of  the  fusiform 
bacilli  to  moist  heat  has  not  been  determined.     Attempts  were 


182  DANDRIDGE    Al  E  M  O  R  I  A  L 

made  to  settle  this  point  by  heating  ascites  broth  cultures  and 
suspensions  in  0.85  per  cent,  sodium  chloride  solution.  As  the 
controls  in  this  series  often  showed  no  growth,  the  following 
technique  was  adopted : 

Seventy-two-hour  cultures  on  Loeffller's  blood  serum  were 
used.  Anaerobic  conditions  were  suspended  and  the  rubber  stop- 
per and  pyrogallic  acid  plug  replaced  by  sterile  cotton  and  a  rub- 
ber cap.  The  tubes  were  then  suspended  in  a  water  bath  for 
fifteen  minutes  at  50°,  55,°  60°'  and  65°  C.  respectively.  Sub- 
cultures were  made  from  each  tube  and  the  result  obtained  was 
confirmed  by  an  additional  subculture  from  the  first  subculture. 
Controls  were  used  throughout. 

The  bacilli  are  killed  by  exposure  to  moist  heat  for  fifteen 
minutes  at  55°  C.  They  are  not  affected  by  an  exposure  at  .'0° 
C.  for  the  same  length  of  time. 

The  fusiform  bacillus  is  able  to  withstand  the  action  of  anti- 
formin,  1  per  cent,  solution,  for  five  minutes  without  altering  its 
viability.  Sevcnty-tv^^o-hour  cultures  on  Loeffler's  blood  serum 
were  covered  with  the  germicide  for  two  and  five  minutes  respec- 
tively, after  which  they  were  washed  with  sterile  distilled  water. 
The  transplants  showed  luxuriant  growths  in  forty-eight  hours. 
When  the  colonies^  were  covered  with  hydrogen  peroxide,  15  per 
cent,  solution,  for  five  minutes  and  washed  with  sterile  water,  no 
growth  appeared  in  the  subcultures.  A  very  luxuriant  growth 
was  obtained  in  the  transplants  from  colonies  which  had  been 
exposed  to  hydrogen  peroxide  for  one  minute.  Cultures  were 
subjected  to  the  action  of  hydrogen  peroxide  for  one,  five,  ten, 
fifteen  and  twenty  minutes  on  two  different  occasions  to  verify 
the  above  results. 

Inoculation  Experiments. — Two  full-grown  guinea-pigs  were 
inoculated  with  ascites  broth  cultures.  The  first  pig  received  1 
c.c.  of  a  72-hour  culture  intraperitoneally,  and  the  other  1  c.c. 
subcutaneously.  A  w^hite  rat  and  a  wild  rat,  M.  norzvegicus, 
were  given  1  c.c.  intraperitoneally.  A  large  rabbit,  weighing  1560 
gms.,  was  inoculated  with  0.75  c.c.  intravenously.  There  was  an 
entire  absence  of  any  local  symptoms,  and  at  the  autopsy,  thirty 
days  after  inoculation,  no  pathological  conditions  were  visible  in 
these  animals.     The  fusiform  bacillus  was  recovered  from  the 


PETERS  183 

peritoneal  smear  of  the  first  guinea-pig,  but  there  was  no  evi- 
dence of  multipHcation.  Tunnidiff's  results  were  negative  in 
guinea-pig  experiments. 

In  the  review  by  Jungano  and  Distaso  they  conclude  that 
Bacillus  fusiformis  is  pathogenic  for  the  guinea-pig  and  the 
mouse.  The  strain  of  Leiner  was  very  virulent  for  the  lower  an- 
imals, and  one  of  Repaci's  cultures  was  also  pathogenic.  Veillon 
and  Zuber  were  only  able  to  produce  a  very  mild  grade  of  infec- 
tion with  their  strains. 

At  the  present  time  there  seems  to  be  a  difference  of  opin- 
ion as  to  the  relation  of  the  spirochsetes  to  Bacillus  fusiformis. 
Some  authors  believe  that  they  are  different  organisms  entirely, 
and  that  the  presence  of  the  spirochaetes  increases  the  virulence 
of  the  bacilli.  Others  maintain  that  they  are  two  forms  of  one 
organism  in  its  cycle  of  evolution.  Tunnicliff  claims  to  have  ob- 
served spirilla  develop  from  the  fusiform  bacilli  in  her  cultures 
after  they  had  grown  from  two  to  five  days.  I  was  unable  to 
note  spirochsetes  in  any  of  the  cultures.  The  terms  spirilla  and 
spirochaeta  have  been  used  indiscriminately  in  the  literature,  but 
I  think  we  should  adhere  rigidly  to  the  word  spirocheta  because 
the  symbiosis  occurring  in  the  mouth  is  one  of  fusiform  bacilli 
and  spirochsetes.  As  was  mentioned  above,  some  of  the  cultures 
contained  wavy  forms,  but  no  true  spirochsetes  were  demonstra- 
ble.    Ellerman  holds  to  the  same  opinion. 

Future  study  may  show  that  certain  metabolic  products  of 
B.  fusiformis  favor  the  growth  of  the  spirochsetes.  Repaci  iso- 
lated spirilla  (spirochsetes?)  from  the  mouth,  which  he  claimed 
to  be  separate  distinct  organisms  from  B.  fusiformis  by  reason 
of  their  chemical  and  biological  peculiarities.  Furthermore  the 
successful  cultivation  of  Sp.  dentium,  Sp.  refringens  and  T.  pal- 
lidum certainly  seems  to  separate  this  group  of  organisms  from 
any  developmental  forms  of  the  bacilli. 

SUMMARY. 

1.  The  substance  of  this  article  consists  essentially  in  a  pre- 
liminary study,  microscopic  and  bacteriologic,  of  Bacillus  fusi- 
formis. Its  biochemical  properties  with  special  reference  to  its 
action  upon  proteids,  will  be  discussed  later. 


184  DAN  BRIDGE    MEMORIAL 

2.  Two  cases  are  recorded  of  direct  transmission  from  one 
individual  to  another. 

3.  In  two  cases  the  fusiform  bacilH  were  not  accompanied  by 
spirochaetes. 

4.  The  organisms  grow  luxuriantly  upon  Dorset's  egg  medium, 
and  in  various  sugar  broths  containing  a  small  amount  of  de- 
fibrinated  rabbit  blood. 

5.  Mention  is  made  of  its  resistance  to  moist  heat,  antiformin 
and  hydrogen  peroxide. 

In  conclusion  I  wish  to  express  my  gratitude  to  Dr.  Wm.  B. 
\Mierry  for  his  many  helpful  suggestions. 

REFERENCES. 

1  Jungano  and  Distaso :  Lcs  anaerobies,  1910,  p.  155. 

2  Weaver:  Journal  Am.  Med.  Assn.,  1906,  46,  p.  481. 

3  Tunniclifif :  Journal  Infections  Diseases,  190(5,  3,  p.  148. 


THE  KURLOFF-BODY,  A  SPURIOUS  PARASITE.* 


BY  OTTO  V.    IIUIFMANX.   M.D. 


Twenty  years  or  more  have  passed  since  Kurloff  first  observed 
certain  vacuoles  or  cell  enclosures  in  the  protoplasm  of  the  large 
mononuclear  leucocytes  of  the  guinea-pig  while  working  in  Ehr- 
lich's  laboratory.  Since  then  improved  staining  methods  and  dis- 
coveries in  the  field  of  protozoolog}^  have  made  it  possible  to  take 
new  viewpoints  in  regard  to  these  cell  enclosures  which  are  called 
Kurloff-bodies.  Therefore  it  is  not  with  surprise  that  we  find 
Ferrata,  Patella.  Goldhorn,  Schilling  and  others  believing  these 
bodies  to  be  protozoan  in  nature.  Patella,  however,  is  the  only 
one  who  claims  to  have  observed  a  flagellate  develop  from  a 
Kurloff-body,  and  of  course  this  observation  would  put  an  end 
to  all  dispute  if  it  could  be  verified. 

After  Patella  had  observed  a  Kurloff-body  develop  a  flagella 
and  acquire  motility,  he  undertook  to  prove  that  the  Kurloft'-body 
is  an  intracellular  phase  in  the  life  cycle  of  a  flagellate  commonly 
found  in  an  infusion  of  the  greens  which  may  be  fed  to  the 
guinea-pig.  By  isolating  newly-born  guinea-pigs  and  feeding 
them  solely  upon  sterilized  milk  and  bread,  he  succeeded  in  keep- 
ing the  blood  free  of  these  bodies,  but  he  did  not  observe  his  iso- 
lated gxiinea-pigs  beyond  the  age  of  four  months,  because  they 
died.  It  is  important  to  note  along  with  this  that  Jolly  and  oth- 
ers have  found  that  the  Kurloff-body  does  not  appear  in  the  cir- 
culation of  the  guinea-pig  until  it  is  at  least  three  or  four  weeks 
of  age.  Consequent  upon  his  observation  of  the  development  of 
a  flagellate  in  the  blood  and  the  results  he  obtained  in  his  feeding 
experiment,  Patella  jumped  to  the  early  conclusion  that  the  Kur- 
loff-body is  none  other  than  the  intracellular  phase  of  a  flagellate 
which  occurs  in  an  infusion  of  greens.  That  this  was  conjecture 
on  the  part  of  Patella  is  further  shown  by  his  belief  that  the 
Kurloff-body  is  identical  with  the  Leucocytozoa   {Hcemogrega- 

*  From  Parasitology,  vol.  iv,  No.  4,  January  8,  1912. 

185 


186  DANDRIDGE    MEMORIAL 

rina)'^  of  Bentley  and  Adie,  for  he  could  not  have  arrived  at  such 
a  behef  if  he  had  had  any  first-hand  knowledge  of  those  organ- 
isms. Likewise  in  the  controversy  which  ensued  between  him 
and  Pappenheim,  it  was  entirely  irrelevant  to  base  any  argument 
upon  some  rod-shaped  bodies  once  observed  by  Auer  in  a  case  of 
acute  lymphatic  leukemia  in  man,  or  upon  a  flagellated  organism 
observed  by  Loewit  in  the  blood  of  a  patient  post-mortem. 

It  was  Patella's  observation  that  the  KurlolT  bodies  were  most 
numerous  in  the  blood  of  guinea-pigs  confined  in  damp,  filthy 
cages,  along  with  a  similar  observation  of  Balfour,  who  noticed 
that  handling  of  the  rats  and  dampness  of  the  cages  increased  the 
prevalence  of  Hmnogreganina  balfouri,  as  well  as  the  fact  that 
the  Kurloff-body  is  absent  in  the  newly-born  guinea-pig,  that  led 
me  to  investigate  the  parasitic  theory  in  regard  to  these  bodies. 

My  studies  and  experiments  have  been  carried  on  continuously 
for  one  year,  and  I  am  greatly  indebted  to  Professor  Wherry  for 
much  assistance  in  pursuing  the  investigation.  Inasmuch  as  the 
Kurloff-body  was  found  not  to  be  a  parasite,  I  will  simply  out- 
line the  results  of  my  work. 

It  was  my  first  duty  to  corroborate,  if  possible,  the  observa- 
tions of  Patella.  Kurloff-bodies  were  patiently  observed  in  wet 
blood  preparations  for  long  periods  of  time  without  the  reward 
of  seeing  flagella  develop.  As  the  mononuclear  leucocyte  con- 
taining the  Kurloff-body  changes  its  own  form  or  moves,  the 
Kurloff-body  undergoes  a  corresponding  change.  Several  times 
I  was  surprised  to  see  how  active  the  Brownian  movement  of 
particles  of  so-called  haemoconien  became  when  in  the  vicinity  of 
a  Kurloff-body — but  this  was  simply  of  passing  interest.  The 
fHagellate  which  occurs  in  an  infusion  of  lettuce,  endive  or  carrots, 
was  found  to  be  a  species  of  Bodo,  and  the  same  species  was 
found  in  the  contents  of  the  cseca  of  all  the  guinea-pigs  examined. 

With  a  further  view  to  Patella's  theory,  I  examined  the  epi- 
thelium of  the  small  as  well  as  the  large  intestine  for  a  possible 
ectoschizous  or  endoschizous  phase  of  a  parasite,  and  I  likewise 
examined  the  cells  of  the  mesenteric  lymph  nodes.  All  of  the 
guinea-pigs  contained  Kurloff-bodies  in  the  blood,  but  in  none 
did  I  find  a  Kurloff-body  in  the  mesenteric  lymph  nodes. 

*  For  literature  see  Parasitology  (1910),  iii,  71. 


H  U  F  F  M  A  N  N  187 

My  next  procedure  was  to  examine  all  the  organs  of  the  body, 
to  find  in  which  portion  of  the  body  the  Kurloft'-bodies  occur  most 
numerously.  This  was  found  to  be  in  the  pulp  of  the  spleen. 
Here  again  wet  preparations  of  blood  and  spleen  pulp  containing 
many  Kurloff-bodies  of  all  sizes  were  kept  under  observation  for 
more  than  a  month  without  noting  any  development  or  change  in 
the  Kurlofif -bodies.  The  warm  stage  and  incubator  were  used 
to  preserve  some  of  them  at  the  same  temperature  as  that  of  the 
guinea-pig. 

As  Kurloft  observed,  through  very  elaborate  studies  extend- 
ing over  several  years,  that  the  large  mononuclear  leucocytes  were 
not  affected  by  splenectomy,  I  made  no  effort  to  repeat  his  ex- 
periments. 

The  stained  preparations  were  made  from  fresh  blood,  spleen 
pulp,  and  from  the  sealed  specimens  wdiich  had  been  under  ob- 
servation. Various  methods  of  fixation  were  tried — Schaudinn's, 
warm  formalin  vapor,  ether,  acids,  osmic  acid  vapor,  etc.  The 
ordinary  dr>'  blood  film  fixed  by  methyl  alcohol,  dried  and  stained 
by  Giemsa,  gives  the  most  uniform  results,  the  Kurloff-body  be- 
ing stained  a  lighter  shade  of  purple  than  the  nucleus  of  the  mono- 
nuclear leucoc}'te.  If  the  methyl  alcohol  is  applied  to  the  blood 
before  it  has  dried,  or  if  the  Giemsa  solution  is  applied  before 
the  methyl  alcohol  has  entirely  evaporated,  the  Kurloff-body  may 
appear  as  a  sac  containing  precipitated  stain.  If  fixed  w^ith  ether, 
the  Kurloff-body  appears  more  homogeneous  and  stains  more 
nearly  red.  The  smallest  bodies  occur  as  azurophilic  granules, 
one  or  more  in  the  protoplasm  of  the  mononuclear  leucocyte,  and 
suggest  an  Anaplasma-Vike  body.  The  bodies  larger  than  a  gran- 
ule are  stained  a  purplish  color;  several  may  occur  in  one  leuco- 
cyte, and  they  may  indent  the  nucleus.  The  most  common  form 
is  about  equal  to  the  nucleus  in  size,  and  is  frequently  associated 
with  two  or  more  small  vacuoles  in  the  protoplasm  of  the  leuco- 
cyte. A  distinct  non-stained  wall  to  the  Kurloff-body  may  be  evi- 
dent, especially  when  the  body  is  smaller  than  the  nucleus. 

The  fact  that  Kurloft'-bodies  occur  in  greater  quantity  in  fe- 
male guinea-pigs  than  in  male  caused  me  to  make  a  complete  study 
of  the  generative  organs  and  their  secretions  but  no  parasites 
could  be  discovered. 


188  DANDRIDGE    MEMORIAL 

So  far  all  investigation  had  been  based  upon  the  assumption 
that  the  Kurlofif-body  is  a  phase  of  an  homoic  parasite.  As  the 
ecto-parasites  had  never  been  given  any  consideration  as  possible 
transmitters  of  the  supposed  Kurloff-body  parasite,  I  took  as  a 
working  hypothesis  that  the  Kurloff-body  is  an  heteroic  parasite. 
It  was  rather  disquieting  to  begin  with  to  find  that  very  lousy  or 
flea-infested  guinea-pigs  did  not  present  more  Kurloff- bodies  in 
their  blood  than  the  less  lousy  or  less  flea  infested.  As  I  pro- 
gressed in  the  work  I  soon  found  that  Kurloff -bodies  were  present 
in  the  blood  of  all  guinea-pigs — I  never  failed  to  find  them  in  a 
guinea-pig  if  I  continued  the  search  for  several  days.  I  might 
mention  here  with  regard  to  the  differential  counting  of  leuco- 
cytes from  day  to  day  that  the  results  were  quite  variable,  such 
variations  being  dependent  upon  the  factors  of  food,  the  degree 
of  heat  and  friction  applied  to  the  ear  just  before  withdrawing 
the  blood,  the  previous  number  of  times  the  ear  had  been  cut  and 
how  recently;  but  in  general  the  proportion  of  polymorpho- 
nuclear forms  to  the  mononuclear  forms  is  about  equal.  The 
mononuclear  cells  containing  Kurloff-bodies  vary  from  day  to 
day  as  much  as  from  1  to  20  f>er  cent,  of  all  the  leucocytes. 

To  see  what  effect,  if  any,  might  result  from  keeping  guinea- 
pigs  free  from  ecto-parasites,  I  performed  the  following  experi- 
ment. Four  guinea-pigs  were  thoroughly  combed  and  brushed. 
Two  of  them  were  etherized  and  bathed  in  ether,  alcohol,  and 
acetic  acid  solution  so  as  to  kill  all  lice  and  eggs  and  then  naph- 
thalin  was  dusted  and  rubbed  into  their  coat.  This  treatment  was 
found  unnecessary  and  not  as  good  as  the  daily  use  of  pyrethrum 
powder  blown  in  amongst  the  separated  hairs  by  an  insufflator 
and  the  removing  of  all  nits  on  top  of  the  head  by  rubbing  with  a 
solution  of  10-20  per  cent,  acetic  acid.  The  guinea-pigs  were 
placed  separately  in  tin  buckets  which  each  day  were  scalded, 
dried,  and  supplied  with  dry  sterilized  saw-dust  for  bedding.  To 
prevent  the  guinea-pigs  from  becoming  infected  with  lice  the 
buckets  containing  the  animals  were  suspended  from  the  ceiling. 
After  a  few  days  of  such  treatment  I  examined  earh  guinea-pig 
for  ecto-parasites  with  negative  results — but  to  ensure  the  com- 
plete extermination  of  any  lice  that  might  have  been  missed  an 
assistant  was  detailed  to  carefully  examine  the  pigs  and  treat  them 


H  U  F  F  M  A  N  N  189 

with  the  powder  and  fresh  dusty  bedding  every  morning  for 
several  months.  It  was  found  that  the  removal  of  all  lice  made 
no  appreciable  difference  in  the  number  of  Kurloff-bodies  present. 
Two  of  the  females  gave  birth  to  young  under  these  conditions, 
and,  while  the  young  did  not  contain  the  larger,  more  mature 
Kurloff-bodies,  they  were  found  to  harbor  the  smallest  form  of 
Kurloff-body,  i.e.,  the  azurophilic  granule. 

During  the  summer  months  these  four  guinea-pigs  which  were 
free  from  ecto-parasites  were  placed  in  a  wet  muddy  hutch  pro- 
tected by  fine  wire  screening  and  far  removed  from  any  source  of 
infestation.  Within  a  few  days  many  of  the  mononuclear  leuco- 
cytes contained  from  one  to  six  azurophilic  granules  and  within 
a  week  many  of  the  mononuclear  leucocytes  contained  the  largest 
form  of  Kurloft"-body,  i.e.,  the  sac,  much  larger  than  the  nucleus 
which  is  crowded  to  one  side,  containing  granular  matter  and 
small  rod-shaped  bodies.  These  animals  upon  again  being  placed 
in  the  dry  buckets  soon  showed  a  recession  in  the  number  of 
Kurloff-bodies  oresent. 

Furthermore,  I  made  a  complete  study  of  ths  intestinal  con- 
tents, excreta,  and  body  juices  of  a  large  number  of  Gyropus 
gracilis,  G.  oralis,  Ctenocephalus  canis,  Ceratophyllus  fasciatus 
and  Acanthia  lectularia  which  had  fed  on  guinea-pigs  containing 
a  high  percentage  of  Kurloff-bodies.  In  the  case  of  the  lice  and 
their  ova,  they  were  experimented  with  on  the  hypothesis  that  an 
organism  might  be  liberated  when  the  egg  is  ingested  by  the 
guinea-pig;  sealed  preparations  of  lice  and  ova  mixed  with  gas- 
tric juice  were  observed ;  and  a  large  number  of  lice  were  fed  to 
a  guinea-pig  having  few  Kurloft'-bodies,  but  nothing  was  dis- 
covered. 

Another  hypothesis  suggested  itself  to  me  by  finding  in  several 
instances  moulds  and  yeasts  in  the  spleens  of  guinea-pigs  imme- 
diately after  the  removal  of  these  organs  under  aseptic  pre- 
cautions. The  fact  that  yeasts  had  been  found  in  the  spleen  in 
cases  of  blastomycosis  was  encouraging.  I  thought  that  the 
Kurloff-body  might  be  the  result  of  the  chemical  activities 
initiated  by  a  spore  either  living  or  after  its  digestion  by  a  leu- 
cocyte. This  point  of  view  gained  support  from  the  observation 
that  cultures  made   from  blood   alone  always   remained   sterile 


190  DAN  BRIDGE    MEMORIAL 

whereas  cultures  from  the  spleen  occasionally  gave  a  growth  of  a 
yeast  or  mould. 

Much  of  this  work  was  repeated  and  carried  out  with  much 
care,  yet  all  of  the  results  are  conclusive  as  disproving  Patella's 
assertion  that  the  Kurlofif-body  is  an  intracellular  stage  of  a 
flagellate. 

It  is  important  that  all  who  experiment  with  guinea-pigs 
should  be  familiar  with  these  cell  inclusions  which  seem  to  be 
normal  to  the  guinea-pig;  for  I  find  no  less  an  observer  than 
Mary  Rowley,  working  with  the  assistance  of  the  staff  of  the 
Rockefeller  Institute,  interpreting  them  as  caused  by  the  injection 
of  blood  from  a  case  of  fatal  anemia. 

REFERENCES. 

Cesaris-Dcmel,  A.  (1905)  :  Sulla  particolare  struttura  di  alcuni  grossi 
leucociti  mononucleati  della  cavia,  colorati  a  fresco.  Arch,  per  le  Set.  Med., 
XX  ix,  388. 

Ehrlich,  P.,  uiid  Lazarus,  A.  ( 1898)  :  Die  Anamie.  1  Abth.  Normale 
und  path.  Histol.  des  Blutes   (Wien),  p.  56. 

Ferrata  A.  (1907)  :  Ueber  die  plasmosomischen  Korper  und  iiber  eine 
metachromatische  Farbung  des  Protoplasmas  der  mononuclearen  Leuko- 
zyten  im  Blut  und  in  den  blutbildenden  Orp^anen.     Vircli.  Arch.,  clxxxvii. 

Hiss,  P.  H.,  and  Zinsser,  H.  (1910)  :  A  Text-Book  of  Bacteriology 
(New  York),  pp.  617-633.     (For  references  on  blastomycosis.) 

Hunter,  J.  W.  (1910)  :  The  nature  of  peculiar  bodies  found  in  the  leu- 
cocytes of  guinea-pigs.     Univ.  of  Penn.  Med.  Bull. 

Loewit,  M.  (1^8)  :  Ueber  intranucleiire  Korper  der  Lymphocyten  und 
liber  geisselfiihrenJe  Elemente  bei  aknter  Ivmpha'ascher  Leukamie.  Ceii- 
fralbl.  f.  Bakieriol.     1  Abt.     Orig.  xiv,  600. 

Pappenheim,  A.   (1907)  :  Riforma  Med.,  No.  23. 

(1908)  :    Ueber    eigenartige    Zelleinschlusse   bei    Leukamie.      Berl. 

klin.  Woch.,  p.  60. 

Patella,  V.  (1907)  :  Riforma  Med.,  Nos.  8,  9  and  20. 

(1908):  Kurloff'sche  Korper  in  mononuclearen  des  Meerschwein- 

schen  Blutes  und  ihre  protozoische  Natur.     Berl.  klin.  IVoch.,  p.  1846. 

Rawley,  Mary  W.  (1908)  :  A  fatal  anemia  with  enormous  numbers  of 
circulating  phagocytes.     Journ.  Ex  per.  Med.,  vc^    x,  p.  78.     Plate  X,  fig.  6. 

Schilling,  V.  (\9\\)  :  Ueber  die  feinere  Morphologic  der  Kurloff-Kor- 
per  des  Meerschweinchens  und  ihre  Aehnlichkeit  mit  Chlamydozoen-Ein- 
schlussen.     Ccriiralbl.  f.  Bakteriol.     1  Abt.     Orig.  Iviii,  318. 


INVOLUTION  OF  THE  THYMUS  BY  THE  X-RAY.* 


BY  ALFRED  FRIEDLANDER,  M.D. 


At  the  present  time  the  problems  of  thymus  physiology  and 
pathology  are  being  studied  by  numerous  investigators  from 
various  viewpoints.  The  abnormal  constitutional  state,  known  as 
the  status  lymphaticus,  is  receiving  much  attention,  especially 
with  reference  to  its  therapy. 

As  is  well  known,  the  chief  characteristics  of  the  status  consist 
of  an  enlarged  thymus,  general  enlargement  of  the  lymph  node 
groups  in  various  parts  of  the  body,  hypertrophy  of  the  tonsils 
and  of  the  pharyngeal  lyTnphoid  tissues,  and  of  the  intestinal 
follicles,  together  with  enlargement  of  the  spleen.  From  the 
clinical  standpoint,  particularly  with  reference  to  the  production 
of  symptoms  dangerous  to  life,  rhe  enlarged  thymus  is  of  first 
importance.  There  has  been  mu^'h  discussion  as  to  whether  or 
not  a  greatly  enlarged  thymus  can  produce  the  symptoms  of 
thymic  asthma  by  mere  mechanical  compression.  But.  whether 
these  symptoms  are  due  to  such  direct  pressure,  or  whether  there 
is  the  indirect  effect  of  the  enlarged  thymus  pressing  upon  the 
great  vessels  and  nerve  trunks  in  the  so-called  critical  space  of 
Grawitz.  or  whether  finally  there  is  a  true  toxemia  resulting  from 
excessive  internal  secretion  (Svehla's  hyperthymization),  the  fact 
remains  that  it  is  the  enlarged  thymus  which  gives  rise  to  the 
threatening  symptoms. 

It  is  doubtless  true  that  there  are  cases  of  enlarged  thymus 
without  the  complete  syndrome  of  status  lymphaticus,  because  in 
not  a  few  of  the  cases  of  thymic  death  neither  spleen  nor  lymph 
glands  have  been  found  to  be  enlarged.  Indeed,  as  a  matter  of 
fact,  in  typical  cases  of  status  lymphaticus,  symptoms  as  such 
arise  practically  always  as  a  direct  result  of  thymus  enlargement. 
So  far  as  the  production  of  thymus  pressure  symptoms  is  con- 

*  Reprinted  from  Archives  of  Pediatrics.  October,  1911. 

191 


192  DANDRIDGE    MEMORIAL 

cerned,  mechanical  compression,  hyperthymization,  indirect  com- 
pression o£  great  vessels  and  nerves  may  all  be  etiologically 
important,  but  the  point  of  greatest  clinical  concern  is  that  we  have 
life-threatening  symptoms  produced  directly  as  a  result  of  the 
enlarged  thymus. 

This  fact  has  been  recognized  from  the  viewpoint  of  therapy 
because  practically  all  the  therapeutic  efforts  heretofore  have 
been  directed  to  the  relief  of  the  direct  pressure  effects  of  the 
enlarged  thymus.  It  has  long  been  recognized  that  medicines  had 
little  or  no  power  to  relieve  thymic  asthma.  Within  recent  years 
surgical  intervention  in  these  cases  has  therefore  been  sought. 
The  earliest  surgical  procedure  for  the  relief  of  the  pressure 
effects  of  the  enlarged  thymus  consisted  of  the  so-called  thymo- 
pexy,  i.e.,  suturing  the  thymus  to  the  inner  surface  of  the  sternum. 
The  results  following  this  operation  have  not  been  satisfactory, 
and  latterly  it  has  been  superseded  by  actual  thymectomy — the 
removal  of  more  or  less  of  the  gland  itself.  This  operation  has 
been  successfully  performed  a  number  of  times  with  complete 
relief  of  the  pressure  symptoms.  But  the  mortality  of  the  opera- 
tion itself  is  high.  Then,  again,  aside  from  the  danger  of  the 
operation  itself,  it  seems  probable,  in  the  light  of  later  researches, 
that  the  removal  of  all,  or  even  of  a  greater  part,  of  the  thymus 
may  be  fraught  with  grave  danger  to  the  subsequent  development 
of  the  individual.  The  complete  removal  of  the  thymus  during 
the  period  of  its  functional  activity  has  been  followed  in  the  lower 
animals  (rabbits,  guinea-pigs,  dogs)  by  very  marked  changes  in 
the  central  nervous  and  osseous  systems,  so  that  the  animals  have 
not  developed  normally  at  all.  While  the  animals  have  survived 
the  operation  itself,  death  has  subsequently  occurred,  in  many 
instances,  under  circumstances  leaving  no  room  for  doubt  as  to 
the  role  of  the  thymectomy  in  its  production.  While  different 
observers  have  obtained  slightly  different  results,  the  general 
picture  after  thymectomy  has  been  about  the  same.  Thus  the 
findings  of  Basch,^  Lucien  and  Parisot-  and  of  Klose,^  to  mention 
just  a  few  names,  are  all  approximately  alike.  The  results  of 
complete  thymectomy  as  obtained  by  Klose  (loc.  cit.)  in  dogs  are 
as  follows :  "For  the  first  two  or  three  months  after  the  operation 
the  animals  are  apparently  well-nourished — even  over-nourished 


FRIEDLANDER  193 

(stadium  adipositas).  But  after  this  period  there  is  a  marked 
loss  of  weight.  Marked  changes  ensue ;  at  first  slowly,  later  with 
great  rapidity.  The  general  weakness  and  especially  the  weakness 
of  the  bones  becomes  very  marked.  The  animals  do  not  grow; 
become  dwarfed.  The  appetite  remains  voracious.  It  is  difficult 
to  coax  the  dogs  from  their  kennels.  If  they  are  forced  to  move, 
they  stagger  about  aimlessly;  spontaneous  bone  fractures  occur 
frequently.  There  is  marked  tremor.  The  animals  become  dis- 
tinctly idiotic,  attempting  to  eat  stones,  corks,  parts  of  their  own 
bodies.  The  hair  falls  out.  Corneal  ulcers  resulting  in  blindness 
are  common.  The  end  picture  of  thymectomized  animals  is 
always  that  of  coma  thymicum,  and  this  stage  is  reached  in  from 
six  to  fourteen  months  after  the  operation."  There  can  be  no 
question  of  the  gravity  of  the  operation  of  thymectomy,  both  as 
to  immediate  and  secondary  results,  and  this  from  both  clinical 
and  experimental  observation. 

In  July,  1907,  I  reported  a  case  of  status  lymphaticus  with 
enlarged  thymus  successfully  treated  by  the  X-ray.*  I  had  been 
led  to  try  the  X-ray  in  this  case  because  of  the  work  of  Heinecke^ 
on  the  effect  of  the  X-ray  on  lymphoid  tissue  (to  be  referred  to 
later).  Since  this  time  several  similar  cases  have  been  reported, 
four  from  this  city.  In  October,  1910,  Rachford®  reported  two 
more  cases,  one  of  which  was  seen  by  me  also.  The  value  of  the 
X-ray  in  cases  of  status  lymphaticus  with  enlarged  thymus  may 
now  be  considered  as  established.  It  is  a  noteworthy  fact,  that 
although  only  the  region  of  the  thymus  is  exposed  to  the  X-ray, 
the  effects  of  the  treatment  are  manifest  not  only  on  the  thymus, 
but  on  the  spleen  and  lymph  glands  as  well.  With  the  idea  of 
investigating  this  finding  experimentally  and  with  the  further  idea 
of  elaborating  the  technique  of  the  use  of  the  ray  in  these  cases, 
this  experimental  study  of  thymus  involution  was  undertaken. 

The  radiologic  part  of  the  work  was  done  by  Dr.  Sidney 
Lange,  radiographer  of  the  Cincinnati  Hospital,  and  all  actual 
details  of  the  X-ray  treatment,  measurement  of  the  tubes,  cur- 
rents, etc.,  were  under  his  supervision. 

Technique. — After  some  preliminary  investigation,  we  decided 
to  t?e  rabbits  in  our  work.  In  each  series,  rabbits  of  one  litter 
we^e  chosen,  and  in  each  series  one  rabbit  was  retained  untreated 


194  DAN  BRIDGE    MEMORIAL 

as  a  control.  By  a  very  ingenious  arrangement  of  Dr.  Lange's, 
the  animals  were  so  placed  in  relation  to  the  tubes  that  only  the 
region  of  the  thymus  and  the  immediate  surroundings  were  ex- 
posed to  the  action  of  the  X-ray.  Particular  care  was  taken  to 
see  that  the  region  of  the  spleen  could  not  come  within  the  focus 
of  the  X-ray, 

The  experiments  were  purposely  varied.  Thus  in  one  series 
each  animal  (except  the  control)  received  only  one  exposure  of  a 
measured  current.  The  animals  were  then  allowed  to  live  varying 
lengths  of  time  in  order  that  possible  differences  in  the  gland 
might  have  time  to  develop.  In  another  series,  the  animals  re- 
ceived varying  numbers  of  treatments,  with  two  or  three  days 
interval  between  exposures.  In  the  next  series  the  time  of  the 
exposure  was  changed.  In  another  series  all  animals  were  given 
excessive  doses  frequently  repeated,  the  attempt  being  made  to 
induce  complete  atrophy. 

TABLE  I. 

Series  I. — Rabbits  of  a  litter  seven  weeks  old.  Each  treatment 
time  15  minutes.  Current  2  milliamp.  Tube= Walter  5.  Dis- 
tance (anode  to  skin)  6  inches.    Aluminum  and  leather  filter. 

Weight  of 
Number  or  Animal 


Desi.-jnation 

Before 

After 

Weight  of 

of  animal 

Treatment. 

Treatment. 

Thymus.                      Remarks. 

1.  Control 

? 

750.00 

0.55 

2.  R.  B. 

760.00 

840.00 

0.32 —  9  treatments  over  3^  weeks 

3.  R.  E. 

675.00 

6S0.00 

0.11 — 12  treatments  over  4^  weeks 

4.  R.  Ba. 

740.00 

790.00 

0  00 — 15  treatments  over  5^  weeks 

5.  Control 

? 

755.00 

0.44 

Series  IL — Rabbits  of  a  litter  four  weeks  old.   Each  treatment 
time  20  minutes.     Current  2  milliamp.     Tube^ Walter  4.     Each 

animal   except   controls  received  twelve   treatments   over   three 
weeks. 

Weight  of 
Number    or  Animal 

Designation               Before  After  Weisht 

of  Animal.                 Treatment.  Treatment.  of  Thymus.                  Remarks. 

1.  Control                 —  275.00  0.22 

2.  Wh.    B.           330.0  355.00  0  025  Killed  at  end  of  3i/ weeks 

3.  Wh.  H.            275.0  340.00  0.02    Killed  at  end  of  4^/^  weeks 

4.  R.  E.                290.0  355.00  0.01     Killed  at  end  of  5     weeks 

5.  Control                 —  315.00  0.17 


FRIEDLANDER 


195 


TABLE  II. 

Series  III. — Five  rabbits  of  a  litter  four  weeks  old.  Each 
animal,  except  the  controls,  received  fifteen  treatments  on  suc- 
cessive days,  each  treatment  lasting  fifteen  minutes.  Current  2 
milliamp.  Tube=Walter  4.  Distance  (anode  to  i-kin)  10  inches. 
In  this  series,  the  thymus  in  each  of  the  treated  animals  disap- 
peared completely  under  the  treatment.  There  v^as  left  merely  a 
small  mass  of  fat  and  connective  tissue,  without  any  glandular 
substance.  The  over-exposure  had  been  purposely  done  in  order 
to  see  whether  this  result  could  be  obtained. 

Series  IV. — In  this  series  each  treated  rabbit  was  given  a 
single  exposure  only.  The  time  of  exposure  in  each  case  was  720 
milliamper-seconds.  Tube=Walter  4.  Distance  10  inches.  The 
animals  were  all  treated  on  the  same  day  and  then  killed  after 
lengthening  periods  of  time. 


Number  or 
Designation 
of   Animal 

Weight  of 
.\nimal    before 
Treatment. 

Weight     T 
At 
Autopsy. 

ime   of  Autopsy 

after 
Treatment. 

Weight 

of 

Thymus. 

Weight 
of  Spleen. 

2.  Br.  W. 

3.  R.  B. 

4.  R.   B. 

5.  R.  E. 

6.  Control 

568.00 
568.00 
450.CO 

410.00 
430.00 
600.00 
538.00 
454.00 

24  hours. 

72  hours. 
144  hours. 
216  hours. 

0.27 
0.30 

0.20 
0.11 
0.24 

0.50 
0.33 
0.35 
0.38 
0.45 

Animals  of 

a  litter  five 

weeks  old. 
TABLE 

III. 

Series  V. — Animals  of  a  litter  four  weeks  old.  In  this  series 
each  treatment  lasted  ten  minutes.  Current  2  milliamp.  Tube^ 
Walter  4.  Distance  8  inches.  The  treatments  were  given  daily 
on  successive  days,  but  the  number  of  treatments  varied  for  the 
different  animals.  All  of  these  animals  were  killed  two  weeks 
after  the  treatments. 


W'eight 

Number  or 

of  Animal. 

Weight 

Number  of 

Weight 

Weight 

Designation 

Before 

at 

Treatments 

of 

of 

of  Animal. 

Treatment. 

Autopsy. 

Given. 

Thymus. 

Spleen. 

7.  R.  E. 

315.00 

30^.00 

3 

0.05 

0.19 

8.  L.  E. 

315.00 

335.00 

2 

0.05 

0.20 

9.  R.  B. 

310.00 

332.00 

4 

?  (Shred) 

0.18 

13.  L.  C. 

315.00 

335.00 

4 

0.06 

0.25 

14.  Control 

— 

450.00 

— 

0.12 

0.35 

196  DAND  RIDGE    MEMORIAL 

Two  of  the  animals  of  this  series,  to  which  five  and  six  treat- 
ments respectively  had  been  given,  were  found  dead  in  the  cages 
one  morning.  For  fear  that  post-mortem  changes  might  cloud 
the  findings,  these  animals  were  excluded  from  the  series. 

In  the  last  series,  only  a  few  exposures  were  given,  but  these 
were  given  on  successive  days. 

Throughout  the  experiments  the  animals  were  weighed  before 
any  treatments  were  given,  and  again  at  autopsy,  in  order  that  we 
could  be  sure  that  no  changes  in  the  thymus  could  be  ascribed  to 
malnutrition  of  the  animal.  Loss  of  weight  of  the  animals  was 
observed  but  twice  in  all  our  experiments,  amounting  in  one  case 
to  30  g.  (1-19  of  body  weight)  and  in  the  other  to  10  g.  (1-31  of 
body  weight). 

Skin  burns  were  never  induced,  except  in  the  animals  of 
Series  III.,  which  had  purposely  been  over-treated. 

The  current  most  generally  used  was  2  milliamp.  The  tube 
usually  measured  Walter=4.  Distance  (anode  to  skin)  varied 
from  6  to  10  inches  in  the  different  series. 

At  the  autopsy,  the  thymus  in  each  case  was  carefully  dis- 
sected out,  weighed,  then  immediately  immersed  in  Zenker's  solu- 
tion. In  the  later  series  the  spleen  and  adrenal  glands  were 
likewise  removed,  the  spleen  in  each  case  being  weighed  before 
immersion  in  the  preserving  fluid. 

The  details  of  the  series  can  be  seen  in  the  accompanying 
tables,  but  the  following  special  points  may  be  noted.  (Tables  I., 
II  and  III). 

Diminution  of  the  weight  of  the  thymus,  both  absolute  and 
relative,  to  the  body  weight  of  the  animals  (as  compared  with  the 
controls),  was  constant.  This  loss  of  weight  was  proportionate 
(a)  to  the  number  of  exposures  (Series  I)  ;  (b)  to  the  length 
of  time  which  elapsed  between  the  treatment  and  the  autopsy 
(Series  II,  Series  IV).  In  Series  IV,  where  each  animal  received 
only  one  treatment,  the  weight  of  the  thymus  decreased  almost 
in  direct  proportion  to  the  length  of  time  intervening  between 
exposure  and  autopsy. 

In  Series  III,  where  each  animal  received  fifteen  treatments 
on  successive  days,  each  treatment  lasting  fifteen  minutes,  the 


FRIEDLANDER  197 

thymus  in  each  case  disappeared  completely  under  the  treatment. 
There  was  left  merely  a  small  mass  of  fat  and  connective  tissue 
without  any  glandular  substance  whatever. 

In  Series  IV  and  V  the  spleen  and  adrenals  were  removed  at 
autopsy.  The  adrenals  were  not  weighed.  The  spleens  were. 
In  Series  IV,  where  each  animal  received  a  single  treatment  only, 
the  relation  of  spleen  weight  to  body  weight  in  the  control  ani- 
mal was  1 :9(X).  In  the  animal  killed  twenty- four  hours  after  ex- 
posure this  relation  was  as  1 :820;  animal  killed  after  seventy-two 
hours,  1:1300;  animal  killed  after  144  hours,  1:1800;  animal 
killed  after  216  hours,  1 :1600. 

A  similar  loss  of  weight  in  the  spleen,  though  not  quite  as 
marked,  was  found  in  the  animals  of  Series  V. 

Microscopic  technique  and  findings :  The  organs  to  be  studied 
were  fixed  in  Zenker's  fluid,  hardened  in  alcohols  and  imbedded 
in  paraffin.  The  stains  ordinarily  used  were  Van  Gieson,  hema- 
toxylon-eosin,  Mallody's  aniline  blue  and  Borel's. 

The  thymus:  To  sum  it  up  briefly,  the  effect  of  the  X-ray 
upon  the  thymus  is  that  it  induces  a  replacement  fibrosis. 

By  varying  the  number  and  the  intensity  of  exposures  given 
and  the  length  of  time  the  animal  is  permitted  to  live  after  treat- 
ment, it  is  possible  to  induce  any  degree  of  fibrosis,  from  the  very 
slightest  up  to  a  complete  disappearance  of  all  glandular  tissue. 
Indeed,  by  giving  the  animals  very  intense  exposures  on  suc- 
cessive days  we  found  it  possible  to  cause  a  complete  disappear- 
ance of  the  gland,  the  animals  being  killed  directly  after  the  last 
treatment.  There  was  found  in  these  animals  only  a  small  amount 
of  fat  and  fibrous  tissue.     (Series  III). 

That  the  X-ray  has  an  elective  action  on  lymphoid  tissue  was 
pointed  out  in  1903  by  Heinecke.^  He  found  that  in  young  ani- 
mals (rabbits,  guinea-pigs  and  dogs)  changes  in  the  spleen  oc- 
curred very  promptly  after  exposure  to  the  X-ray.  There  was  a 
marked  increase  of  pigment,  disintegration  of  many  cells  and 
reduction  in  the  size  of  the  Malpighian  bod?fes.  In  addition  there 
was  rarefaction  of  the  cellular  elements  of  the  spleen  pulp.  An- 
alogous changes  to  those  seen  in  the  spleen  follicles  occurred  in 
all  the  lymphoid  groups  of  the  body,  in  the  follicles  of  the  intes- 
tine and  in  the  thymus. 


198  DANDRIDGE    MEMORIAL 

IMore  recently,  Aubertin  and  Bordet"  and  Rudberg^  have 
studied  the  thymus  involution  after  X-ray  in  detail.  Rudberg 
indeed  has  found  that  changes  in  the  thymus  02cur  as  early  as 
three  and  one-half  hours  after  exposure.  "There  is  a  marked  dis- 
integration of  the  small  th^Tnus  cells  at  this  time,  the  nuclear 
fragments  being  taken  up  by  the  reticular  epithelium  or  dissolved 
in  the  intercellular  spaces  in  from  twelve  hours  to  two  days.  Ac- 
cording to  the  length  and  intensity  of  the  exposure  there  may  be 
a  complete  disappearance  of  the  lymphoid  elements,  the  gland 
taking  on  an  epithelioid  character."  ^ 

These  early  changes  we  have  been  able  to  follow  distinctly. 
Furthermore,  we  have  succeeded  in  inducing  various  grades  of 
fibrosis,  up  to  the  complete  involution  of  the  gland,  by  varying 
the  number  of  exposures,  the  degree  of  intensity  of  current  and 
the  intervals  between  treatments,  and  the  lapsed  time  after  treat- 
ment to  autopsy.  This  fact  is  of  prime  clinical  and  therapeutic 
importance. 

Taking  the  control,  untreated  animals  as  normal,  with  a  thy- 
mus of  course  unchanged,  we  have  been  able  to  induce  gradually 
increasing  fibrosis  up  to  the  stage  w^iere  the  thymus  is  completely 
sclerotic.  A  short  resume  of  the  histologic  findings  in  this  series 
c  f  increasing  degrees  of  fibrosis  of  the  thymus  follows : 

1.  Animal  2  Br  \V.     One  exposure  only  of  720  ]\I.  A.  Sec. 
The  section  shows  that  cortex  and  medulla  are  still  distinct. 

There  is  a  beginning  disappearance  of  the  small  thymus  cells, 
especially  in  the  medulla,  the  cortex  being  still  normal.  There 
are  distinct  evidences  of  phagocytosis  in  some  of  the  medullary 
reticular  cells. 

2.  Animal  3  R  B.  One  exposure  only,  of  72'd  M.  A.  Sec. 
Animal  killed  seventy-two  hours  after  exposure.     (Series  IV.) 

The  beginnings  of  the  fibrosis  are  already  to  be  seen.  There 
are  areas  in  which  the  reticular  structure  shows  up  much  more 
prominently  than  in  the  normal  gland,  because  of  the  destruction 
of  the  small  thymus  c6lls.  In  such  areas,  the  cells  of  epithelioid 
type  predominate ;  indeed,  the  tissue  begins  to  assume  an  epithe- 
lial aspect. 

3.  Animal  4  R  B.  One  exposure  only,  of  720  M.  A.  Sec. 
Animal  killed  144  hours  after  exposure.     (Series  IV\) 


F  R  I  E  D  L  A  N  D  E  R  199 

There  is  a  distinct  increase  in  the  amount  of  intercellular  sup- 
porting tissue,  and  the  fibrils  of  connective  tissue  are  more  dis- 
tinct. But  in  this  thymus  the  evidences  of  degeneration  are  also 
distinct.  Mitotic  figures  are  common,  especially  in  the  nuclei  of 
the  reticular  cells,  and  there  are  areas  scattered  throughout  the 
gland,  showing  definite  evidence  of  regeneration.  (The  clinical 
significance  of  this  regeneration  of  the  thymus  after  exposure  to 
the  X-ray  will  be  referred  to  later.) 

4.  Animal  2  B.  Nine  exposures,  each  fifteen  minutes,  given 
over  a  period  of  three  and  one-half  weeks.     (Series  I.) 

Large  areas  of  glandular  substance  are  replaced  by  fibrous 
tissue,  parts  of  which  show  enlarged  spindle-shaped  cells.  In 
other  portions  the  fibrous  tissue  is  denser,  and  the  young  connec- 
tive tissue  cells  are  no  longer  to  be  seen.  The  bands  of  fibrous 
tissue  not  only  encircle  the  thymus  lobules,  but  also  run  in  be- 
tween the  lobules,  separating  them.  Along  some  of  the  interlob- 
ular fibrous  bands  there  are  well-marked  hemorrhages.  There 
is  some  thickening  of  the  adventitia  of  the  vessels.  The  Hassall 
corpuscles  are  well  preserved. 

5.  Animal  4  R  E.  Twelve  exposures,  each  of  twenty  min- 
utes, over  three  weeks.  Killed  after  four  and  one-half  weeks. 
(Series  II.) 

The  whole  gland  is  sclerotic  to  the  extent  that  fully  half  the 
tissue  is  fibroid.  There  is  marked  perivascular  fibrosis.  The 
Hassall  corpuscles,  though  present,  are  atrophic.  There  is  a  ten- 
dency for  the  thymus  tissue  remaining  to  be  arranged  in  groups 
or  nests. 

6.  Animal  9  R  B.  Four  exposures  daily,  but  given  on  suc- 
cessive days.  Each  of  ten  minutes.  Killed  two  weeks  after  last 
exposure.     (Series  V.) 

It  is  noteworthy  that  very  intense  fibrosis  occurred  here  after 
only  four  exposures.  But  these  were  given  on  successive  days. 
The  Hassall  corpuscles  show  a  marked  degeneration  (kerato- 
hyalinization).  The  thymus  cells  remaining  in  many  instances 
show  fragmentation.  The  fibrosis  here  is  much  more  marked 
than  in  the  case  of  the  animal  just  preceding,  though  this  rabbit 
received  twelve  exposures.    But  these  were  given  over  a  period  of 


200  DANDRIDGE      MEMORIAL 

three  weeks,  while  the  four  exposures  in  the  case  of  Animal  9  R  B 
were  given  on  successive  days, 

7.  Animal  4  R  Ba.  Fifteen  exposures.  Ea'^h  of  fifteen  min- 
utes, over  five  and  one-half  weeks.     (Series  I). 

The  fibrosis  is  very  marked,  and  the  tendency  to  grouping  of 
the  remaining  thymus  cells  is  very  distinct.  Rudberg  has  noticed 
a  similar  change  in  the  thymus  of  animals  receiving  prolonged  ex- 
posure. 

8.  Animal  3  Wh.  H.  Twelve  exposures.  Twenty  minutes  each. 
Over  three  weeks,  killed  at  end  of  five  weeks.     (Series  II.) 

A  further  degree  of  fibrosis  is  represented  here.  While  this 
animal  received  only  twelve  exposures,  as  contrasted  with  fifteen 
in  the  case  of  the  preceding  animal,  the  intervals  between  the  ex- 
posures were  shorter. 

9.  Animal  13  L  C.  Four  exposures  on  successive  days.  Each 
of  ten  minutes.  Killed  two  weeks  after  last  exposure.  (Series  V.) 

This  thymus  showed  complete  fibrous  involution.  The  gland 
was  converted  into  thick  bands  of  fibrous  tissue  without  any  re- 
maining evidences  of  reticular  structure.  This  animal  received 
only  four  exposures,  each  of  ten  minutes'  duration.  But  they 
were  given  on  successive  days. 

Table  IV. 

Schema,  illustrating  increase  of  fibrous  tissue  approaching 
complete  fibrosis,  as  illustrated  in  cases  on  opposite  page : 

From  the  clinical  standpoint  of  treatment  of  cases  of  status 
lymphaticus  with  enlarged  thymus  by  the  X-ray,  it  must  of  course 
be  important  to  determine  how  the  treatment  should  be  given  with 
reference  to  the  number  of  treatments,  duration  of  each  treat- 
ment and  order  of  succession.  Partly  with  this  end  in  view,  the 
experiments  were  varied  in  the  different  series  of  animals.  Tak- 
ing the  degree  of  fibrosis  as  a  guide,  the  following  table  has  been 
prepared,  showing  the  gradations  of  change  from  the  normal  con- 
trol organ  to  the  practically  completely  fibrotic  one.    (Table  IV.) 

A  study  of  the  table  shows  the  following  facts: 

The  glands  showing  the  least  change  were  those  to  which  only 
one  exposure  was  given.    Of  the  three  in  this  group,  the  increase 


FRIEDLANDER 


201 


in  fibrosis  was  (as  was,  of  course,  to  be  expected)  in  direct  pro- 
portion to  the  length  of  time  elapsing  from  the  exposure  to  the 
autopsy.  Thus  the  animal  killed  twenty-four  hours  after  ex- 
posure showed  less  fibrosis  than  the  one  killed  after  seventy-two 
hours,  and  this  one  in  turn  less  than  the  one  killed  after  144 


Normal  Gland, 


COMPLETE 
FIBROSIS. 

0. — Normal  animals.     Not  treated.     Controls. 

1. — 2  Br.  W.  One  exposure,  720  M.  A.  Sec.  Killed  twenty-four  hours 
after  treatment.     (Series  IV.) 

2. — 3  R.  B.  One  exposure,  720  M.  A.  Sec.  Killed  seventy-two  hours 
after  treatment.     ''Series  IV.) 

3. — 4  R.  B.  One  exposure,  720  M.  A.  Sec.  Killed  144  hours  after  treat- 
ment.    (Series  IV.) 

4. — 2  B.  Nine  exposures,  each  of  fifteen  minutes,  over  three  and  one- 
half  weeks.     (Series  I.) 

5. — 4  R.  E.  Twelve  exposures,  each  of  twenty  minutes,  over  three 
weeks.    Killed  at  end  of  four  and  one-half  weeks.     (Series  II.) 

5. — 2  Wh.  E.  Twelve  exposures,  each  of  twenty  minutes,  over  three 
■weeks.     Killed  at  end  of  three  and  one-half  weeks.     (Series  II.) 

6. — 9  R.  Ba.  Four  exposures  on  successive  davs,  each  of  ten  minutes. 
Killed  two  weeks  after  last  exposure.     (Series  V.) 

7. — 4  R.  Ba.  Fifteen  exposures,  each  fifteen  minutes,  over  five  and  one- 
half  weeks.     (Series  I.) 

8. — 3  Wh.  H.  Twelve  exposures,  each  of  twenty  minutes,  over  three 
weeks.    Killed  at  end  of  five  weeks.     (Series  II.) 

9. — 13  L.  C.  Four  exposures  on  successive  days,  each  of  ten  minutes. 
Killed  two  weeks  after  last  exposure.     (Series  V.) 


202  DAN  BRIDGE    M  E  Al  O  R  I  A  L 

hours.  It  is  to  be  noted  that  the  current  used  in  these  single 
exposure  cases  was  stronger  than  in  the  other  experiments.  The 
next  thymus  in  the  scale  of  fibrosis  was  that  of  an  animal  receiv- 
ing nine  exposures  of  fifteen  minutes  each  over  three  and  one- 
half  weeks.  The  changes  here  were  a  little  less  pronounced  than 
in  the  cases  of  the  next  two  animals,  each  receiving  twelve  ex- 
posures of  twenty  minutes  each,  over  three  weeks,  these  animals 
being  killed  at  the  end  of  three  and  one-half  and  four  and  one- 
half  weeks,  respectively. 

A  greater  degree  of  fibrosis  was  induced  in  an  animal  re- 
ceiving only  four  exposures,  each  of  only  ten  minutes.  But  it 
is  significant  that  these  treatments  were  given  on  successive  days, 
the  animal  being  killed  two  weeks  after  the  last  treatment. 

The  next  degree  of  fibrosis  was  indticed  by  fifteen  exposures 
of  fifteen  minutes  each,  over  five  and  one-half  weeks,  and  the 
following  one  by  twelve  exposures  of  twenty  minutes  each,  over 
three  weeks.  The  last  degree  of  fibrosis,  complete  involution, 
was  induced  by  four  exposures  on  successive  days,  the  animal 
being  killed  two  weeks  after  the  last  treatment.  This  animal  re- 
ceived exactly  the  same  number  of  treatments  as  did  Animal  4  R 
Ba,  of  the  same  series,  in  which  the  degrees  of  fibrosis  induced 
was  also  very  high. 

While  it  would,  of  course,  be  decidedly  unsafe  to  make  abso- 
lutely sweeping  deductions  from  such  a  table  as  this,  certain  sig- 
nificant facts  may  at  least  be  noted  as  being  of  therapeutic  value. 

Intense  fibrosis  may  be  induced  by  a  comparatively  small  num- 
ber of  exposures  if  they  are  given  on  successive  days. 

When,  therefore,  the  symptoms  of  pressure  from  the  en- 
larged thymus  are  very  urgent,  and  when  there  is  evidently  very 
marked  mechanical  obstrtiction  from  the  enlarged  thymus,  the 
X-ray  treatments  should  be  pushed,  being  given  on  successive  days 
to  get  quick  results  The  shorter  the  interval  between  the  treat- 
ments, the  more  marked  the  results  obtained.  Four  exposures 
on  successive  days  (Animal  13  L  C)  gave  a  greater  degree  of 
fibrosis  than  fifteen  exposures  over  five  and  one-half  weeks.  (Ani- 
mal 4  R  Ba.) 

It  is  probable  that  the  age  of  the  animal  would  have  something 
to  do  with  the  case  of  produ'^tion  of  fibrosis  under  treatment. 


F  R  I  E  D  L  A  X  D  E  R  203 

The  animals  receiving  only  four  treatments  (on  successive  days) 
with  high  degrees  of  fibrosis,  were  rabbits  four  weeks  old.  In 
cases  of  thymic  asthma,  therefore,  occurring  in  infants,  the  ear- 
lier treatment  is  begun  the  better  the  outlook. 

Where  the  symptoms  are  not  so  urgent,  where  therefore  there 
is  not  the  necessity  for  producing  either  so  great  a  degree  or  so 
rapid  induction  of  fibrosis,  ihe  treatment  may  be  given  at  longer 
intervals. 

Clinically  it  has  been  noted  that  the  symptoms  of  thymic, 
asthma,  which  gradually  disappear  under  X-ray  treatment,  tend 
to  recur  after  varying  periods  of  time  in  some  cases.  This  is 
doubtless  to  be  explained  on  the  basis  of  partial  regeneration  of 
the  thymus  after  partial  fibrosis  has  been  induced.  We  are  able 
to  explain  this  and  to  demonstrate  it  in  our  experimental  series; 
because  we  have  been  able  to  show  definite  evidences  of  regener- 
ation of  thymus  tissue  in  partially  fibrotic  glands.  W^here  such 
symptoms  of  thymic  asthma  recur  therefore,  it  means  that  the 
artificial  involution  of  the  gland  has  not  been  carried  far  enough, 
indicating  that  a  further  course  of  X-ray  treatment  is  needed. 

For  instance,  in  the  first  case  reported  by  Rachford  (already 
alluded  to),  it  is  noted  that  after  the  first  and  immediate  im- 
provem.ent  under  the  X-ray,  the  child  had  "at  intervals  of  about 
three  months  three  very  slight  attacks  characterized  by  cough  and 
dyspnea,  which  occurred  without  apparent  cause  and  which  were 
promptly  relieved  by  one  or  more  mild  X-ray  treatments." 

As  is  well  known,  enlargement  of  the  spleen  and  lymph  node 
groups  of  the  body  constitute  constant  phenomena  in  true  cases 
of  status  lymphaticus.  In  the  original  case  of  status  (reported  by 
me  in  1907),  which  was  treated  by  the  X-ray,  it  was  noted  that 
though  only  the  region  of  the  thymus  was  exposed  to  the  action  of 
the  X-ray,  there  was  a  marked  decrease  in  size  of  the  lymph  glands 
and  of  the  spleen  coincidentally  with  the  shrinkage  of  the  thy- 
mus. The  same  condition  was  observed  in  the  case  under  the 
supervision  of  Rachford  and  myself,  and  subsequently  reported 
by  Rachford.® 

In  order  to  explain  if  possible  or  at  least  to  confirm  this  find- 
ing, experimentally,  the  spleens  of  the  rabbits  were  examined 
systematically  in  our  later  series.  Attention  has  already  been  called 


204  DANDRIDGE    MEMORIAL 

to  the  fact  that  the  region  of  the  spleen  was  absolutely  protected 
from  the  direct  action  of  the  rays  in  all  our  cases. 

A  marked  reduction  in  the  size  of  the  spleen  in  relation  to  the 
body  weight  of  the  animals  was  observed  in  our  treated  animals, 
as  will  be  seen  by  reference  to  Tables  II  and  III.  But  in  addi- 
tion to  this  there  was  a  very  marked  change  in  the  histologic 
picture  of  the  spleen  of  the  treated  animals. 

In  his  original  studies  on  the  effects  of  the  X-ray  on  lymphoid 
structures,  Heinecke^  found  that  in  young  animals,  changes  in 
the  spleen  occurred  very  promptly.  There  was  a  marked  in- 
crease of  pigment,  disintegration  of  many  cells,  and  reduction  in 
the  size  of  the  Malpighian  corpuscles.  In  addition  there  was  a 
rarefaction  of  the  cellular  elements  of  the  spleen  pulp.  Now 
these  are  precisely  the  changes  which  occurred  in  the  spleens  of 
our  treated  animals.  The  reduction  in  number,  size  and  clear- 
ness of  outline  of  the  Malpighian  corpuscles  is  very  striking,  and 
in  our  series  was  found  to  be  correlated  in  degree  to  the  amount 
of  fibrosis  in  the  corresponding  thymus.  The  disintegration  of 
the  spleen  cells  (as  studied  under  high  magnification)  was 
marked.  The  reduction  in  number,  size,  and  clearness  of  outline 
of  the  Malpighian  corpuscles  is  very  pronounced.  That  some  re- 
lation exists,  functionally  speaking,  between  thymus  and  spleen 
now  seems  assured.  Indeed,  in  some  of  the  later  researches  on 
thymus  physiology  the  spleen  is  definitely  referred  to  as  the  "or- 
gan of  substitution"  for  the  thymus  after  the  period  of  functional 
activity  of  the  latter.  Without  attempting  any  discussion  of  this 
question,  it  may  be  noted  as  significant  that  both  clinically  and 
experimentally,  change  in  size  (and  in  our  experimental  series  in 
histologic  picture)  of  the  spleen  occurs  pari  passu  with  the  arti- 
ficial involution  of  the  thymus.  And  this  though  in  both  in- 
stances the  region  of  the  spleen  is  absolutely  protected  from  any 
direct  action  of  the  X-ray.  In  our  later  series  the  adrenals  of 
the  rabbits  were  carefully  examined,  but  no  histologic  change  was 
found  in  the  adrenals  of  any  of  the  treated  animals. 

The  experiments  certainly  seem  to  justify  the  belief  that  in 
the  X-ray  we  have  a  therapeutic  agent  of  great  value  in  the  treat- 
ment of  enlarged  thymus.  The  fact  that  in  our  clinical  cases  of 
status  lymphaticus  concomitant  changes  occur  in  other  portions 


FRIEDLANDER  205 

of  the  lymphoid  tissues  of  the  body,  that  experimentally  we  were 
able  to  induce  changes  in  the  spleen,  both  go  to  prove  that  the 
X-ray  is  a  valuable  agent  in  the  treatment  of  status  lymphaticus 
itself.  For  if  by  exposing  only  the  region  of  the  thymus  to  the 
action  of  the  Roentgen  ray,  we  can  cause  diminution  in  size  of 
the  spleen  and  of  the  lymph  nodes,  can  change  a  lymphocytic  to 
a  normal  blood  picture,  it  would  seem  that  we  have  made  some 
distinct  advance  in  the  treatment  of  status  lymphaticus.  Cer- 
tainly the  X-ray  is  far  safer  than  the  dangerous  operation  of 
thymectomy.  Apparently  it  is  not  followed  by  subsequent  ill 
effects,  either.  Thus  it  is  interesting  to  note  that  at  this  writing, 
the  first  patient  treated  by  the  X-ray  (over  six  years  ago)  is  in 
excellent  condition.  He  shows  absolutely  no  evidence  of  any- 
thing like  a  lymphatic  constitution.  His  development  has  been 
perfectly  normal,  his  general  health  excellent.  The  other  cases 
are  all  in  excellent  condition  also. 

SUMMARY. 

1.  Internal  treatment  is  of  no  avail  in  cases  of  enlarged 
thymus  or  status  lymphaticus. 

2.  Surgical  intervention,  i.e.,  thymectomy,  has  been  success- 
ful in  a  number  of  cases.  But  (a)  the  operation  is  an  exceed- 
ingly dangerous  one.  (6)  Complete  thymectomy  in  lower  ani- 
mals is  invariably  followed  by  subsequent  developmental  changes, 
manifested  in  the  central  nervous  and  osseous  systems  chiefly, 
and  invariably  leading  to  the  death  of  the  animal. 

3.  In  the  X-ray  we  have  an  agent  which  is  at  the  same  time 
safe  and  efficacious  in  the  treatment  of  enlarged  thymus  and 
status  lymphaticus. 

4.  By  means  of  the  X-ray  it  is  possible  to  induce  not  only 
an  involution  of  the  thymus,  but  also  in  cases  of  status  lymphat- 
icus to  reduce  the  size  of  the  spleen,  of  the  lymph  nodes  and  to 
change  the  lymphocytic  blood  picture  to  the  normal  one. 

5.  By  variation  in  the  number  and  frequency  of  X-ray  ex- 
posures, it  is  possible  to  bring  about  the  involution  with  varying 
degrees  of  rapidity.  Where  the  symptoms  of  thymic  asthma  are 
urgent,  the  exposures  can  be  given  on  successive  days,  thus  in- 
ducing prompt  results. 


206  DANDRIDGE  MEMORIAL 

6.  Experimentally  it  has  been  shown  to  be  possible  to  induce 
any  degree  of  fibrosis  of  the  thymus  from  the  very  slightest  to 
absolutely  complete    sclerosis. 

7.  Clinically  the  dosage  of  X-ray  can  therefore  be  regulated 
according  to  the  necessities  of  the  case. 

8.  A  thymus  partially  involuted  by  the  X-ray  is  capable  of 
regeneration.  The  danger  of  loss  of  thymus  function  (as  in  the 
case  of  complete  thymectomy)  is  thus  obviated  and  the  metab- 
olic changes  after  thymectomy  averted. 

9.  The  use  of  the  X-ray  in  these  cases  is  without  danger 
to  the  individuals,  as  proved  by  the  subsequent  normal  develop- 
ment of  our  treated  cases. 

It  is  a  pleasure  to  acknowledge  a  debt  of  gratitude  to  Dr.  P. 
G.  Woolley,  for  his  interest  in  and  critical  supervision  of  the  ex- 
perimental work. 

REFERENCES. 

1.  Basch.    Jahrb.  f.  Kindcrhk.,  1906,  Ixiv,  1903,  Ixvii. 

2.  Lucien  and  Parisot.    Arch,  de  Med.  Exp.,  1910,  No    10. 

3.  Klose.    Arch.  f.  Kinderhk.,  1910,  Iv. 

4.  Friedlander.    Archives  of  Pediatrics,  Julj-,  1907. 

5.  Heinecke.     Mucnch.  Med.   ^voch.,  1903,  p.  2.090. 

6.  Rachford.    American  Journal  of  Medical  Science.  October,  1910. 

7.  Aubertin  and  Bordet.      Centralb.  f.  Inn.  Med.,  1909,  xxx,  976. 

8.  Rudberg.    "Thymus  Involution  after  X-Ray."     U p.'-.ola,  1909. 

9.  Rudberg    quoted    bv    Pappenheimer.      "Histology    of    the    Thymus." 
Journal  of  Medical  Research,  February,  1910. 


THE  ROLE  OF  ACIDOSIS  OF  THE  TISSUE  AS  A  FAC- 
TOR IN  THE  PRODUCTION  OF  AN  ATTACK 
IN  PAROXYSMAL  HEMOGLOBINURIA. 


BY  OSCAR  BERGHAUSEN,  B.A.,   M.D. 


During  January,  1910,  a  colored  man  suffering  from  paroxysmal 
liemoglobinuria  was  admitted  to  the  Cincinnati  Hospital.  He 
gave  a  history  of  passing  blood-colored  urine,  particularly  upon 
exposure  to  the  cold.  While  producing  congestion  above  the  el- 
bow in  order  to  obtain  blood  from  the  median  vein  for  a  Wasser- 
mann  determination,  it  was  noticed  that  at  such  times  there  was 
obtained  a  blood  serum  which  was  laked.  This  led  me  to  inves- 
tigate more  closely  the  effect  of  carbonic  acid  gas  upon  the  v/ashed 
corpuscles  obtained  from  both  the  patient  and  from  a  normal  in- 
dividual, and  the  effect  of  salts  in  controlling  this  hemolysis  was 
studied.  This  forms  a  complete  report  of  the  work  which  was 
done,  and  which  was  briefly  referred  to  by  jMartin  H.  Fischer  in 
his  work  on  "Edema." 

History. — Patient,  H.  C,  colored  male,  aged  twenty-six,  sin- 
gle, entered  Cincinnati  Hospital,  December  31,  1909,  suft'ering 
from  pains  in  the  back. 

Personal  History. — Did  not  have  ordinary  diseases  of  child- 
hood. Rheumatism  about  six  years  ago.  Returned  from  the 
South  about  one  year  ago  where  he  had  been  for  several  years. 
While  there  he  had  a  chill  every  evening,  for  which  he  took 
quinine.  Several  years  ago  he  says  he  was  troubled  with  gall- 
stones. Admits  syphilis  and  gonorrhea.  Is  not  a  heavy  drinker. 
Denies  the  use  of  drugs  or  highly  seasoned  foods. 

Onset. — Patient  has  been  working  on  the  river,  where  he  was 
exposed  to  the  rough  weather.  Was  com.pelled  to  labor  hard  and 
perspired.  Eight  days  ago  the  patient  began  having  pains  in  left 
side  in  region  of  kidney.  Says  that  his  urine  was  bloody  for 
several  days. 

Present  State. — On  admission,  a  fairly  well  developed  man. 
Temperature  97°.     Conjunctiva  yellow  tinged. 

Chest  Inspection. — Negative. 

Palpation. — Vocal  fremitus  increased  in  right  upper  lobe. 

207 


208  DANDRIDGE  MEMORIAL 

Percussion. — Diminished  resonance  over  right  upper  lobe. 

Auscultation. — Prolonged  expiration  and  roughened  breath- 
ing over  right  upper  lobe.    Moist  rales  over  the  entire  lung  area. 

Heart. — Nothing  abnormal  found. 

Abdomen. — Pain  in  left  lumbar  region.  X-ray  shows  nothing 
abnormal  about  the  kidney  or  ureter. 

January  9,  1910.  Patient  has  intermittent  attacks  of  hemo- 
globinuria, which  usually  come  on  in  the  afternoon.  During  the 
intervals,  the  urine  is  clear.  Cystoscopic  examination  shows  that 
the  hemoglobinuria  is  bilateral.  He  was  now  transferred  from 
the  surgical  to  the  medical  service.  During  the  next  five  days  he 
passed  bloody  urine  only  once.  On  January  15,  1910  the  blood 
picture  showed — 

RedTcells    3,200,000 

White   cells    7,000 

Polys     59.0  per  cent. 

Large    lymphocytes     14.5  per  cent. 

Small  lymphocytes 19.0  per  cent. 

Eosinophiles     4.0  per  cent. 

Transitional    3.8  per  cent. 

No  abnormal  cells,  red  cells  are  anemic.  During  or  immed- 
iately after  an  attack  the  blood  picture  seems  to  approximate  the 
normal.  About  three  days  after  one  attack,  the  count  showed 
polys,  46.0  per  cent. ;  lymphocytes,  large  and  small,  50-0  per  cent. ; 
eosinophiles,  4.0  per  cent. 

The  temperature  would  vary  from  subnormal  and  normal  to 
99.2°-100.2°  F.  On  January  29,  it  reached  104°  F.,  due  to  an 
attack  of  acute  tonsillitis,  which  quickly  subsided  and  was  not 
accompanied  by  an  attack  of  hemoglobinuria.  The  fecal  examin- 
ation, made  on  January  10,  1910,  showed  a  yellow  formed  stool, 
no  free  fat,  a  few  meat  fibres  well  digested,  no  parasites.  Blood 
culture,  negative. 

Noguchi  deviation  of  complement  test,  distinctly  positive. 

The  patient  improved  while  in  the  hospital,  the  treatment 
being  rest,  warmth,  light  diet.  Potassium  iodide  was  given  in- 
ternally. The  attacks  became  fewer  in  number,  and  the  patient 
was  discharged  on  February  26,  1910,  feeling  much  improved  in 
health. 

EXAMINATION   OF  THE   URINE. 

On  January  2,  1910,  the  urine  passed  was  light  amber  in  color, 
spectroscopic  examination  was  negative,  likewise  the  guaiac,  bile 
and  Ehrlich's  aldehyde  reaction  tests. 

On  January  3,  1910,  the  urine  was  black  in  appearance,  the 
spectroscopic  examination  gave  a  double  line,  one  in  the  green 
and  one  in  the  yellow  fluids,  the  guaiac  test  was  positive,  the  bile 


B  E  R  G  H  A  U  S  E  N  209' 

test  was  unsatisfactory,  and  Ehrlich's  aldehyde  reagent  gave  a 
distinct  scarlet  color  in  the  cold,  with  the  corresponding  spectrum- 

On  January  5,  the  urine  was  smoky  in  color,  the  spectroscopic 
examination  was  negative,  the  aldehyde  reaction  was  positive,  a 
scarlet  color,  in  the  cold.  Microscopic  examination  showed  the 
presence  of  granular  casts,  no  corpuscles  and  no  parasites. 

On  January  6,  a  Bier's  congestive  bandage  was  applied  to 
both  upper  arms  over  a  period  of  ten  minutes.  In  two  and  one- 
third  hours  the  urine  passed  was  dark,  contained  albumin,  spec- 
troscopic examination  showed  presence  of  hemoglobin,  and 
Ehrlich's  aldehyde  reaction  was  positive  in  the  cold. 

On  January  7,  the  morning  urine  was  amber  in  color,  spectro- 
scopic examination  was  negative,  no  albumin,  the  aldehyde  re- 
action was  positive  in  the  cold.  The  sediment  snowed  casts,  but 
no  corpuscles. 

EXAMINATION   OF  THE  BLOOD  SERUM   AND  CORPUSCLES. 

On  January  7,  at  noon,  a  congestive  bandage  was  applied  and 
the  blood  removed  from  the  arm  vein.  A  portion  of  this  blood 
was  defibrinated  at  the  bedside,  and  the  serum  after  centrifuging 
was  distinctly  laked.  Another  portion  was  set  aside  in  a  sterile 
test  tube  and  kept  at  — 10°  C,  and  still  a  third  portion  was  kept 
at  37°  C.  The  blood  serum  which  separated  in  both  tested  tubes 
was  distinctly  hemolytic.  The  blood  serum  was  then  examined 
for  the  presence  of  syphilitic  antibodies  according  to  the  Noguchi 
modification,  and  a  distinct  inhibition  in  hemolysis  was  obtained. 
The  patient's  corpuscles  were  then  again  obtained,  washed  three 
times  in  normal  salt  solution  and  subjected  to  the  action  of  an- 
other syphilitic  serum  as  follows : 


Corp. 

suspension. 

Normal 
salt  solution. 

Syphilitic 
serum — Webb. 

Hemolysis. 

1. 

2. 
3. 

1  drop 
1  drop 
1  drop 

1  c.c. 
1  c.c. 
1  c.c. 

0     c.c. 
0.5  c.c. 
1.0  c.c. 

Since  no  hemolysis  resulted  after  incubation  at  37°  C.  and 
allowing  to  stand  until  the  next  morning,  it  was  determined  to 
test  the  action  of  another  syphilitic  serum  after  adding  comple- 
ment, which  was  done  January  8,  1910: 

Patient's  Guinea- 
washed  pig  comp.  Syphilitic  Salt 
corpuscles.  40perct.  serum — Webb.  solution.            Result. 

1.  1  drop                0.1  0.1  c.c.  1.0  c.c. 

2.  1  drop               0.1  0.2  c.c.  0.8  c.c. 

3.  1  drop               0.1  0.4  c.c.  0.6  c.c. 

4.  1  drop                0.1  0.8  c.c.  0.2  c.c. 


210  DANDRIDGE   MEMORIAL 

The  controls  using  the  patient's  washed  corpuscles  without 
added  syphilitic  serum,  also  my  own  washed  corpuscles  in  place 
of  the  patient's  in  the  above  experiment,  were  also  negative. 
Evidently  the  syphilitic  bodies  or  antibodies  played  no  great  part 
in  the  production  of  the  hemolysis. 

OTHER  FACTORS  WHICH  MAY  INDUCE  AN  ATTACK- 

The  effect  of  cold  in  producing  an  attack  of  hemoglobinuria 
was  spoken  of  by  the  patient  himself.  It  was  cleaily  shown  above 
that  by  simply  placing  a  congestive  bandage  upon  the  upper  arm, 
at  first  the  blood  serum  become  laked,  and  later  the  urine  was 
colored  red  and  contained  hemoglobin.  It  was  further  found 
that  by  simple  catheterization,  a  typical  chill  was  developed,  which 
was  later  followed  by  the  passing  of  a  highly-colored  urine  con- 
taining blood  coloring  matter. 

The  increase  of  temperature  associated  with  the  attacks  can 
be  readily  explained  by  the  action  of  the  liberated  hemoglobin 
upon  the  system.  Vaughan  proved  this  beautifully  in  animals 
when  he  found  that  laked  blood  corpuscles  of  either  man  or 
rabbit  after  filtration  cause  an  elevation  of  temperature  when  in- 
jected into  rabbits  either  intra-abdominally  or  intravenously. 

HOW    IS   HEMOLYSIS  ACCOMPLISHED? 

The  presence  of  a  specific  amboceptor  which  has  to  do  with 
causing  a  solution  of  the  corpuscles  in  vivio  is  assumed  by 
many  authors.  Donath  and  Landsteiner  were  the  first  to  show 
that  in  the  cooled  extremity  the  patient's  corpuscles  were  acted 
upon  by  the  specific  amboceptor,  and  thus  prepared  were_  acted 
upon  by  the  complement  in  the  general  circulation,  leading  to 
hemolysis.  This  was  confirmed  by  later  observers.  Hymans  later 
showed  that  the  blood  serum  of  hemoglobinuric  cases  contained 
specific  substances  which  in  the  presence  of  free  CO2  acted^upon 
the  corpuscles  of  the  patient  at  lower  temperatures  (8°-16°  C.), 
leading  to  their  hemolysis.  They  state  further  that  the  blood 
serum  and  corpuscles  of  a  normal  individual  are  not  hemolized 
in  this  manner.  The  Donath-Landsteiner  phenomenon  was  not 
observed  in  every  case,  however.  Cases  of  paroxysmal  hemo- 
globinuria are  reported  in  which  sufficient  cooling  of  an  extremity 
did  not  lead  to  an  attack.  Likewise  by  placing  a  congestive 
bandage  about  an  extremity  attacks  have  not  always  been  pro- 
duced. This  has  been  explained  by  some  as  due  to  the  fact  that 
following  one  attack  the  complement  has  been  absorbed  and 
must  again  be  produced  in  sufficient  amount  in  order  to  cause 
hemolvsis. 

Evidently   existing   theories    do   not   account    for   the  many 
variations  which  occur  in  the  blood  stream  of  patients  suffering 


BERGHAUSEN  211 

from  paroxysmal  hemoglobinuria.  All  observers  seem  to  pay 
especial  attention  to  the  specific  amboceptors,  to  the  complement, 
and  a  few  to  the  presence  of  free  carbonic  acid,  but  none  seem 
to  regard  the  presence  of  other  dissolved  substances,  particularly 
the  salts,  as  playing  any  important  factor-  With  the  object  of 
ascertaining  the  part  which  the  salts  play  in  the  phenomenon  of 
hemolysis,  the  following  experiments  were  undertaken: 

ACTION  OF  ACIDS  ON  THE  CORPUSCLES  AND  SERUM. 

Lactic  Acid.. 
Washed      Normal 
corpuscles,  salt  sol.  Lactic  acid.  Result. 

1.         1  drop         1  c.c.         1  drop  cone.  sol.        Immediate    hemolysis    and 

conversion. 
Gradual  hemolysis. 
Gradual  more   rapid. 
Gradual   more  rapid. 

ATMOSPHERE  OF   COo. 

(a)  Serum. 

By  passing  a  current  of  dried  COo  gas  into  a  test  tube  con- 
taining hemoglobinemic  serum,  a  rapid  reduction  took  place.  By 
exposing  diluted  and  undiluted  hemoglobinemic  serum  contained 
in  small  Petri  dishes,  to  an  atmosphere  of  dried  COo  gas,  a  re- 
duction likewise  took  place,  the  rapidity  depending  upon  the 
dilution.  The  controls  made  by  exposing  similar  serum  to  the 
action  of  air  over  night  suffered  no  reductions. 

(b)  Corpuscles  in  Normal  Salt  Solution. 


2. 

1  drop 

1  c.c. 

1  drop  (1-10  dil.) 

3. 

1  drop 

1  c.c. 

2  drops  (1-10  dil.) 

4. 

1  drop 

1  c.c. 

4  drops  (1-10  dil.) 

Patient's 

washed 

Normal 

Atmosphere  of 

corpuscles. 

salt  sol. 

CO2  exposure. 

Result. 

1. 

5  drops 
Jan.  7,  1910. 

5  c.c. 

Over  night 

Complete    hemolysis. 

2. 

5  drops 
Jan.  10,  1910. 

5  c.c. 

Three  hours 

Slight   hemolysis. 

3. 

5  drops 
Jan.  12,  1910. 

5  c.c. 

One  hour 

Complete   hemolysis. 

My  own  corpuscles  similarly  washed  and  treated  showed  no 
hemolysis  in  one  hour,  complete  hemolysis  by  the  next  morning. 

Both  lactic  and  carbonic  acid  cause  rapid  solution  of  the  cor- 
puscles with  reduction,  the  rapidity  depending  upon  the  dilution. 
This  was  to  be  expected.  Normal  salt  solution  delayed  this 
action.  The  corpuscles  obtained  from  the  patient  suffering  from 
paroxysmal  hemoglobinuria  seemed  to  be  less  resistant  to  the 
action  of  the  carbonic  acid  gas,  even  in  the  presence  of  normal 
salt  solution. 


212  DANDRIDGE   MEMORIAL 

(c)   Corpuscles  in  Sodium  Citrate  Solution. 

Defibrinated  patient's  corpuscles  were  washed  three  times  in 
1-5  per  cent,  sodium  citrate  solution.  Five  drops  were  added  to 
5  c.c.  citrate  solution  and  exposed  to  CO2  atmosphere  for  three 
hours  at  room  temperature.  They  were  then  taken  out  and 
centrifuged.  No  hemolysis  had  taken  place.  Patient's  corpus- 
cles in  normal  salt  solution  similarly  exposed  showed  complete 
hemolysis.  Corpuscles  similarly  treated  with  sodium  citrate  so- 
lution and  normal  salt  solution,  and  exposed  to  room  temperature, 
showed  no  hemolysis. 

The  experiment  was  repeated,  using  my  own  corpuscles,  and 
similar  results  were  obtained. 

The  corpuscles,  both  from  the  patient  and  myself,  after  wash- 
ing in  1.5  per  cent,  sodium  citrate  solution  and  exposing  to  CO2 
atmosphere  for  three  hours,  were  again  washed,  suspended  in 
normal  salt  solution  and  exposed  to  CO,  gas.  Complete  hemolysis 
resulted  in  three  hours. 

(d)   Corpuscles  in  Normal  Salt  Solution  and  Sodium  Citrate 
Solution  in  CO. 2  Atmosphere. 


Washed 

corpuscles, 

Normal 

Sodium 

After  four 

5  drops. 

salt  sol. 

citrate  sol. 

hours'  exposure. 

1. 

Patient's 

5.0  c.c. 

0 

C.H. 

2. 

Delaney's 

S.O  c.c. 

0 

C.H. 

3. 

Patient's 

1.0  c.c. 

0.5     C.C. 

No  H. 

4. 

Delaney's 

1.0  c.c. 

0.5    c.c. 

No  H. 

S. 

Patient's 

1.0  c.c. 

0.75  c.c. 

Trace    H. 

6. 

Delaney's 

1.0  c.c. 

0.75  c.c. 

No  H. 

7. 

Patient's 

1.0  c.c. 

1.0    c.c. 

No  H. 

8. 

Delaney's 

1.0  c.c. 

1.0    c.c. 

No  H. 

The  results  of  these  experiments  would  tend  to  show  that 
corpuscles  in  normal  salt  water  suspension  are  readily  hemolized 
in  an  atmosphere  of  COo,  and  that  the  addition  of  a  slight  amount 
of  another  neutral  salt  is  sufficient  to  inhibit  this  action. 

(e)   Corpuscles  plus  Serum  in  an  Atmosphere  of  COo. 

Washed  Exposure 

corpuscles,  Delanej^'s  three  hours ; 

5  drops.  serum.  room  temperature. 

1.  Patient's  0.3  c.c.  No  H. 

2.  Delaney's  0.3  c.c.  No  H. 

In  this  case  a  normal  serum  was  sufficient  to  prevent  the 
hemolytic  action  of  CO,  upon  the  corpuscles  obtained  both  from 
the  patient  and  another  normal  individual. 


B  E  R  G  H  A  U  S  E  N  213 


DEDUCTIONS. 


In  the  above  experiments  it  was  noticed  that  the  corpuscles 
of  patient  suffering  from  paroxysmal  hemoglobinuria  were  some- 
what less  resistant  to  an  atmosphere  of  carbonic  acid  gas,  as  com- 
pared to  corpuscles  from  a  normal  individual.  This  difference 
was  not  very  marked,  however-  The  chief  difference  lies  in  the 
blood  serum  of  the  patient. 

Contrary  to  the  findings  of  Ilymans,  it  was  found  that  normal 
corpuscles  in  normal  salt  water  suspension  were  also,  although 
more  slowly,  hemolized  in  an  atmosphere  of  carbonic  acid  gas. 
Sodium  citrate  solution',  strength  1.5  per  cent.,  was  sufficient  to 
prevent  hemolysis  of  both  the  patient's  and  normal  human  cor- 
puscles in  atmosphere  of  carbonic  acid  gas  at  room  temperature. 
Apparently  the  salt  concentrations  of  the  blood  serum  is  the 
factor  which  determines  whether  the  corpuscles  shall  be  hemo- 
lized or  not.  As  shown  above,  normal  serum  has  sufficient  salt 
dissolved  to  prevent  hemolysis  of  both  the  patient's  and  normal 
corpuscles  in  an  atmosphere  of  CO,  at  room  temperature. 

Krokiewicz  states  that  inactivated  (55°  C.)  serum  from  a 
hemoglobinuric  patient,  no  longer  hemolizes  the  patient's  cor- 
puscles in  an  atmosphere  of  CO,,  after  adding  fresh  human 
serum  as  complement.  By  adding  this  serum  he  merely  increased 
the  salt  concentration  of  the  serum  which  previously  was  poor 
in  salts. 

The  paroxysmal-like  attacks  have  been  variously  ascribed  to 
the  action  of  cold,  congestion  and  trauma,  locally  or  remotely 
produced.  It  would  appear  that  changes  locally  in  the  tissues 
must  be  necessary  before  a  state  of  hemoglobinemia  or  hemoglo- 
binuria can  be  produced.  In  view  of  the  fact  that  cold,  trauma 
and  passive  congestion  may  all  lead  to  an  attack,  and  since  the 
three  conditions  are  associated  with  the  production  of  an  ex- 
cessive acidity  of  the  tissues,  it  is  not  unreasonable  to  suppose 
that  the  organic  acids  thus  formed  play  some  part  directly  in  the 
production  of  the  attacks.  The  corpuscles  may  be  less  resistant, 
they  may  be  subject  to  the  action  of  a  specific  hemolysen,  and 
yet  an  additional  factor  acting  locally  in  the  tissues  seems  neces- 
sary for  an  attack  to  be  produced.  In  the  presence  of  the  proper 
salt  concentration  the  corpuscles  are  protected  against  the  hemo- 


214  DAN  BRIDGE  MEMORIAL 

lytic  action  of  any  organic  acids.  This  naturally  suggests  the 
giving  of  neutral  salts  as  a  therapeutic  agent  to  prevent  the  onset 
of  attacks  in  patients  suffering  from  paroxysmal  hemoglobinuria. 
In  conclusion,  I  wish  to  thank  Dr.  E-  W.  Mitchell,  the  staff 
physician,  for  his  kindness  in  permitting  me  to  report  this  case^ 
also  Prof.  Martin  H.  Fischer  for  valuable  suggestions. 

REFERENXES. 

Martin  H.  Fischer:  Edema.     Philadelphia,  1910,  pp.  173. 

Donath  and  Landsteiner :  Munchener  Med.  Wochenschrift,  1904. 

Erich  Meyer  and  E.  Emmerich :  Ueber  paroxysmale  Hamoglobinurio. 
Deutsches  Archiv  f.  klin.  Med.,  1909,  Bd.  96. 

Hymans  v.  d.  Bergh :  Blut  Untersuchungen  iiber  die  Hamolyse  bis  der 
paroxvsmale  Hamoglobinurio.     Berl.  klin.  Woch.,  1909,  Nos.  27  and  35. 

Czernecki :  Wien.  Klin.  Woch.,  1909,  No.  42. 

Krokiewicz:  Wien.  Klin.  Woch.,  1911,  No.  14. 

V.  C.  Vaughan,  J.  C.  Gumming,  J.  H.  Wright:  Zeitschrift  f.  Immunit., 
May  13,  1911,  pp.  473. 


THE  EFFECTS  PRODUCED  BY  NUMEROUS   INJEC- 
TIONS OF  INDOL  AND  TYROSIN  IN  EXPERI- 
MENTAL ANIMALS:    A  CONTRIBUTION 
TO  THE  STUDY  OF  CHRONIC  INTES- 
TINAL INDICATIONS.* 


L.   H.   XEWBURGH,   M.D.,  AND  PAUL  G.   WOOLLEY,   M.D., 


The  term  "chronic  intestinal  auto-intoxication"  was  first  applied 
by  Herter  to  a  pathological  state  arising  from  an  excessive  ab- 
sorption of  substances  resulting  from  the  action  of  bacteria  on 
the  contents  of  the  lower  bowel.  Herter  demonstrated  that  two 
groups  of  bacteria  could  be  distinguished  by  their  biochemical  re- 
action in  the  normal  adult  feces.  The  one  group  is  fermentative, 
the  other  putrefactive.  The  products  of  the  fermentative  group 
(chiefly  lactic  and  acetic  acids)  are  innocuous,  whereas  the  putre- 
factive group  manufacture  substances  which  are  thought  to  be 
capable  of  giving  rise  to  symptoms,  when  absorbed  from  the 
bowel  in  sufficient  concentration.  Certain  putrefactive  bacteria 
are  always  present  in  the  adult  feces.  The  colon  bacillus  is  found 
in  varying  numbers  from  infancy  onward,  but  although  putre- 
factive, is,  according  to  Herter,  not  the  chief  offender-  He  be- 
lieved that  the  harmful  decomposition  products  w^ere  for  the 
most  part  dependent  upon  the  overabundance  of  anaerobic  micro- 
organisms. Using  Gram's  method  of  staining  and  appropriate 
anaerobic  methods  of  cultivation,  he  found  that  persons  suffering 
from  excessive  intestinal  putrefaction  harbored  enormous  num- 
bers of  anaerobes  in  the  colon  and  that  the  B.  aerogenes  capsulatus 
(Welchii)  w^as  usually  the  dominant  organism.  Often  typical 
colon  bacilli  were  absent.  As  the  condition  improved,  the  colon 
bacilli  returned  and  the  gas  bacilli  and  related  organisms  were 
greatly  decreased  in  numbers.  Among  the  products  formed  by 
the  putrefactive  bacteria  from  the  contents  of  the  colon  are  indol, 
skatol,  methyl  mercaptan,  and  many  other  decomposition  pro- 

*  Reprinted  from  The  Lancet-Clinic,  April  13,  1912. 

215 


216  DANDRIDGE  MEMORIAL 

ducts  which  have  not  yet  been  isolated.  It  is  thought  that  the 
absorption,  in  sufficient  concentration,  of  members  of  this  group 
of  substances  may  give  rise  to  a  variety  of  symptoms. 

Forchheimer  has  studied  this  subject  from  the  clinical  side. 
Among  the  symptoms  noted  by  him  in  an  analysis  of  seventy- 
seven  cases  from  his  general  practice  are  stomach  troubles,  de- 
bility, constipation,  flatulence,  headache,  neuralgic  pains,  Rigg's 
disease,  albuminuria,  indicanuria,  cardiac  neuroses,  vascular  and 
myocardial  changes,  muscular  pains,  and  in  most  cases  a  moderate 
secondary  anemia. 

Huchard,  in  his  studies  on  arteriosclerosis,  approached  the 
.subject  from  a  somewhat  different  angle;  but  he  also  was  im- 
pressed with  the  importance  of  intoxications,  presumably  of 
intestinal  origin,  as  an  etiological  factor  in  arteriosclerosis.  He 
taught  that  arteriosclerosis  is  usually  the  result  of  arterial  hyper- 
tension ("presclerosis"),  and  that  the  latter  is  usually  called  forth 
by  an  intoxication.  The  intoxication  is  of  alimentary  origin  and 
results  from  the  functional  insufficiency  of  the  kidney  which 
prevents  certain  products  of  albuminous  digestion  from  being 
eliminated.  He  supports  this  contention  by  citing  some  experi- 
ments which  his  assistant,  Tournier,  performed.  The  latter 
found  that  the  urine  of  persons  suffering  from  presclerosis  is  less 
toxic  than  normal  urine.  That  is,  there  is  a  retention  of  toxic 
products.  When  the  patient  is  fed  on  a  milk-vegetable  diet  the 
pressure  falls  to  normal  and  other  toxic  symptoms  disappear. 
Thus,  we  gather  from  Huchard's  writings  that  a  diet  containing 
the  usual  amount  of  meat  may  be  a  source  of  symptoms,  but  only 
when  the  kidney  is  insufficient-  He  does  not  tell  us  what  the 
toxic  substances  are  or  how  they  are  formed.  Moreover,  his 
conclusions  are  subject  to  criticism  because  of  the  quite  obvious 
fallacy  of  his  statement  that  decreased  toxicity  of  the  urine  is 
evidence  of  retention  of  toxic  bodies. 

Our  experiments  had  the  following  objects  in  view: 

1.  To  see  what  lesions,  if  any,  we  could  produce  by  injecting 
certain  of  these  bodies,  thought  to  have  toxic  properties,  into 
animals,  over  long  periods ;   and 

2.  To  see  what  relation  these  bodies  bear  to  the  condition 
named  presclerosis  by  Huchard. 


NEWBURGHANDWOOLLEY  217 

In  order  to  carry  out  the  first  object  we  have  injected  white 
rats  intraperitoneally  with  saturated  aqueous  solutions  of  indol. 
We  have  chosen  indol  because  it  was  present  in  almost  every 
instance  in  the  urine  in  Forchheimer's  cases,  and  because  it  is 
formed  in  large  amounts  by  the  putrefactive  bacteria  when  grown 
on  proteid  media,  and  because  some  of  the  constitutional  effects 
attributed  to  it  in  experimental  work  are  observed  in  clinical  cases 
in  which  it  is  present.  That  the  indol  was  continuously  in  circu- 
lation is  shown  by  the  fact  that  the  urine  always  gave  a  strong 
indican  reaction. 

We  also  ran  a  parallel  series,  using  tyrosin  instead  of  indol. 
The  tyrosin  series  had  a  somewhat  different  basis.  In  our  pre- 
liminary report,  we  stated  that  we  had  been  led  to  suspect  that 
the  pigmentation  of  Addison's  disease  might  be  a  result  of  varia- 
tion in  either  the  content  of  the  chromaffin  tissues  in  tyrosinase, 
or  in  the  overabundance  of  tyrosin  or  some  related  substance  in 
the  body.  The  idea  arose  from  a  suggestion  of  v.  Fiirth  that 
melanin  and  related  bodies  are  the  result  of  the  action  of  tyro- 
sinase or  related  oxidases  upon  the  aromatic  constituents  of  the 
protein  molecule,  a  suggestion  which,  as  Adami  says,  has  been 
supported  by  Halle,  who  demonstrated  that  tyrosin  is  converted 
into  adrenalin  by  a  ferment  in  the  adrenal.  Adami  suggests  that 
pigmentation  in  Addison's  disease  is  produced  when  this  ferment 
is  deficient,  that  is,  when  the  tyrosin  is  not  converted  into  ad- 
renalin by  the  adrenal,  but  into  melanin  in  the  skin.  These 
suggestions  induced  us  to  attempt  to  discover  whether  prolonged 
injections  of  tyrosin  would  stimulate  the  adrenals  to  increased 
activity  with  resulting  hypertension,  or  whether  evidences  of 
hyperfunction  being  absent  melanosis  would  result. 

We  also  suspected  that  indol  might  cause  adrenal  changes  for 
these  reasons:  Presclerosis,  whose  chief  symptom  is  increased 
blood  pressure,  is  due,  according  to  Huchard,  as  stated  above,  to 
an  intestinal  intoxication.  Since  adrenalin  raises  blood  pressure, 
and  since  intestinal  intoxication  is  thought  to  raise  the  blood 
pressure,  it  might  be  that  indol  does  this  in  part  or  wholly  through 
its  effect  on  the  adrenal  glands-  For  these  reasons  it  seemed 
advisable  to  run  these  two  series  of  experiments  at  the  same  time. 
In  the  preliminary  report  we  summarized  our  results  as 
follows : 


218  DANDRIDGE  MEMORIAL 

"After  these  injections  (indol  and  tyrosin)  we  found  the- 
medullas  of  the  adrenals  hyperplastic  and  apparently  hypertro- 
phic ;  and  that  evidences  of  chromafifin  activity  increased  in  pro- 
portion to  the  number  of  injections.  The  chrome  reaction  was 
similarly  increased.  We  also  found  very  slight  interstitial  changes 
in  the  kidneys." 

We  now  wish  to  report  what  further  results  we  have  obtained : 
Our  experimental   data  are  given  below.     The   descriptions 
apply  mainly  to  the  adrenal  glands. 

TYROSIN  SERIES. 

Protocol  4. — White  rat,  six  injections  of  1  c.c.  saturated  aque- 
ous solution  of  tyrosin  each  week.    Total  injections,  12. 

No  macroscopic  changes.  Microscopic :  Very  moderate 
amount  of  dilatation  of  sinuses  of  adrenal.  Medulla  solidly 
cellular;  chrome  reaction  distinct;  thickness  of  medulla  72.5; 
average  width  at  cortex  31.0- 

Protocol  5. — White  rat,  six  injections  of  1  c.c.  saturated  aque- 
ous solution  of  tyrosin  each  week.    Total  injections,  21. 

No  macroscopic  changes  other  than  cloudy  swelling  of  liver, 
kidney  and  heart  muscle.  Microscopic:  Islands  of  medullary 
substance  reach  as  far  as  glomerulosa ;  chrome  reaction  brown- 
ish, rather  than  yellow  ;  very  little  dilatation  of  sinuses ;  medulla 
very  solid ;  considerable  fatty  metamorphosis  of  cortex ;  almost 
none  in  medulla.     Thickness  of  medulla  70;   width  of  cortex  31. 

Protocol  12. — White  rat,  six  injections  of  5  c.c.  saturated 
aqueous  solution  of  tyrosin  each  week.     Total  injections  8. 

Mucoid  cystic  tumor  of  lung.  Thyroid  about  twice  normal 
size.  Liver,  spleen,  kidneys,  adrenals,  enormously  congested- 
The  adrenals  have  a  succulent,  translucent  appearance.  On  sec- 
tion they  show  a  soft  chocolate-colored  medulla  occupying  the 
whole  gland,  save  for  a  narrow  rim  of  cortex.  The  darkness  and 
fluidity  of  the  medulla  are  striking.  Microscopic:  Adrenal,  very 
well  marked  chrome  brown  reaction  with  a  considerable  fatty 
change  in  the  medulla ;  cortex  also  shows  fatty  degeneration  and 
well-marked  congestion ;  some  dilatation  of  sinuses  of  medulla, 
though  not  excessive ;  chromaffin,  as  a  rule,  compact.  Thickness 
of  medulla,  70.    Width  of  cortex,  Z7. 

Protocol  7j. — White  rat,  six  injections  of  5  c.c.  saturated 
aqueous  solution  of  tyrosin  each  week.    Total  injections,  13. 

Small  mucoid  cystic  tumor  of  lung.  Liver,  spleen,  kidneys, 
adrenals  enormously  congested.  Other  macroscopic  changes  as 
in  No.  12,  except  that  thyroid  not  enlarged-  Microscopic:  Ad- 
renals, intense  chrome  reaction ;  considerable  fatty  change ;  con- 
siderable dilatation  of  sinuses ;  medulla  has  not  a  compact  appear- 


NEW  BURGH  AND  \V  O  O  L  L  E  Y  219 

ance ;  cortex,  very  moderate  parenchymatous  change ;  some 
islands  of  medtdlary  substance  in  the  cortex.  Thickness  of  me- 
dulla. 50.    Width  of  cortex,  41. 

Protocol  i8. — White  rat,  six  injections  of    5  c.c.  saturated 
aqueous  solution  of  ty rosin  each  week.     Total  injections,  40. 


Tyrosin  Series. 

Rat 
Rat 
Rat 
Rat 
Rat 
Rat 

4—12 
5—21 
12—  8 
13—8 
18-40 
19—50 

injections 
injections 
injections 
injections 
injections 
injections 

1 
1 

5 
5 
5 
5 

Medulla. 

c.c.    each 72.5 

c.c.    each.... 70.0 

c.c.    each 70.0 

c.c.    each.... 50.0 

c.c.   each 66.5 

c.c.    each 66.5 

Cortex. 
31.0 
31.0 
37.0 
41.0 
41.0 
41.0 

Index 
2.3:1 
2.3:1 
1.9:1 
1.2:1 
1.6:1 
1.6:1 

Average 

65.9 

hidol  Series. 

35.3 

1.8:1 

Rat 
Rat 
Rat 

6—12 

7—20 

14—13 

injections 
injections 
injections 

1 
1 
5 

c.c.    each 72.5 

c.c.    each.... 72.5 
c.c.    each.  .  .  .57.5 

30.0 
31.2 
37.5 

2.4:1 
2.3:1 
1.5:1 

Average 

67.5 

Control. 

32.9 

2.0:1 

Rat 
Rat 
Rat 

20-0 
1^-  0 
3—0 

injections 
injections 
injections 

0 
0 
0 

c.c.    each. . .  .60.0 

c.c.    each 60.0 

c.c.    each 45.0 

30.0 
40.0 
25.0 

2.0:1 
1.5:1 
1.4:1 

Average 

55.0 

31.6 

1.7:1 

Salt  Solution. 

Rat 

21—20 

injections 

5 

c.c.    each 62.5 

40.0 

1.3:1 

Adrenals  congested,  most  marked  in  cortex.  Medulla  com- 
pact ;  accumulation  of  chromaffin  substance  in  cells,  giving  an 
appearance  not  seen  in  controls.  Cells  themselves  plump,  so  that 
the  whole  appearance  gives  one  the  im.pression  of  hyperactivity. 
Thickness  of  medulla.  66.5.     \\'idth  of  cortex.  41. 

Protocol  iQ. — White  rat,  six  injections  of  5  cc.  saturated 
aqueous  solution  of  tyrosin  each  week.     Total  injections,  40. 

Appearances  similar  to  those  in  Protocol  18. 

Protocol  6. — White  rat,  six  injections  of  1  c.c.  saturated  aque- 
ous solution  of  indol  each  week.     Total  injections,  12. 

No  macroscopic  lesions.  Microscopic:  xVdrenal  shows  very 
moderate  dilatation  of  the  sinuses ;  apparently  no  clear  yellow 
(lipoid?)  reaction;  solid  compact  arrangement  of  the  chrom- 
affin ;  very  little  congestion ;  cortex  not  remarkable.  Thickness 
of  medulla.  72.'^.     Width  of  cortex,  30. 

Protocol  /. — White  rat.  six  injections  of  1  c.c.  saturated  aque- 
ous solution  of  indol  each  week.     Total  injections,  20. 


220  DAXDRIDGE    MEMORIAL 

No  macroscopic  lesions.  Microscopic:  Adrenals  show  marked 
congestion;  chrome  reaction  very  well  marked.  Cortex  shows 
little  parenchymatous  change;  few  isolated  islands  of  medullary 
substance  in  cortex;  chromaffin  tissue  very  solid.  Thickness  of 
medulla,  72.5.    Width  of  cortex,  31.2. 

Protocol  14. — White  rat,  six  injections  of  5  c.c.  saturated  aque- 
ous solution  of  indol  each  Vv'eek.    Total  injections  13. 

Urine  shows  intense  indican  reaction ;  no  glycosuria.  Adrenals 
on  section  show  a  dark  brown  medulla,  which,  however,  is  not 
soft.  Adrenals :  medulla  moderately  congested  and  of  a  greenish 
brown  color.    Thickness  of  medulla,  57-5.    Width  of  cortex,  37.5. 

COXTROL  SERIES. 

Protocol  J — White  rat.    No  treatment. 

Protocol  16. — W'hite  rat.    No  treatment. 

Protocol  20. — White  rat.    No  treatment. 

Protocol  21. — White  rat,  six  injections  of  5  c.c.  normal  salt 
solution  each  week.    Total  injections  20. 

General  appearance  of  adrenals  not  unlike  those  of  protocol 
3.    Thickness  of  medulla,  62.5.    Width  of  cortex,  40- 

SUMMARY. 

The  measurements  given  were  made  as  follows:  A  Leitz  III 
micrometer  ocular  was  used  with  a  Leitz  3  objective.  The  draw- 
tube  of  the  microscope  was  kept  at  the  same  length  for  all  sec- 
tions. The  width  of  the  cortex  of  each  adrenal  was  read  off 
merely  by  comparing  divisions  on  the  micrometer  scale.  The 
thickness  of  the  medulla  was  read  in  the  same  way.  Several 
sections  were  used  (paraffin  sections  with  hematoxylin  and  eosin 
stain  after  bichromate  fixation  for  each  determination),  and  these 
sections  were  made  transversely  from  the  second  part  of  the 
glands. 

We  should  add  to  the  above  data  that  in  no  case  did  we  observe 
anything  more  than  cloudy  swelling  and  congestion  of  the  glan- 
dular organs  of  the  animals,  and  that  these  changes  were  rarely, 
if  ever,  more  extreme  in  the  controls.  Whenever  any  remark- 
able change  has  presented  itself  it  has  been  noted  in  the  proto- 
cols. 

DISCUSSION, 

The  lengthening  of  the  series  of  experiments  mentioned  in  our 
preliminary  report  shows  that  the  volume  of  the  medullas  of  the 


NEWBURGH  AND  \V  O  O  L  L  E  Y  221 

adrenals  does  not  increase  in  proportion  to  the  number  of  injec- 
tions, nor  to  the  amount  of  substance  injected,  in  either  the  indol 
or  tyrosin  series. 

As  a  matter  of  fact  the  reverse  seems  true.  But  it  also  seems 
possible  that  the  activity  of  the  chromafifin  cells  is  increased. 
However  that  may  be,  there  seems  to  be  no  associated  changes 
in  other  glandular  organs,  and  this  is  especially  interesting  in  the 
case  of  the  liver  and  kidney-  No  blood-vessel  changes  were  ob- 
served in  any  case. 

But  if  there  seems  to  be  no  systematic  increase  in  the  medulla 
it  is  also  true  that  there  does  seem  to  be  relative  increase  in  the 
volume  (estimated  in  width)  of  the  cortex,  and  that  this  appar- 
ent increase  bears  no  direct  relation  to  the  amount  of  lipoid 
metamorphosis.  If  this  should  turn  out  to  be  a  fact  it  will  be  of 
interest  from  the  standpoint  of  the  production  of  epinephrin.  It 
has  been  suggested  that  the  early  stages  of  epinephrin  production 
occur  in  the  adrenal  cortex — that  the  cortex  contains  a  substance 
that  might  be  called  pre-epinephrin,  and  that  the  material  becomes 
epinephrin  only  when  modified  by  the  action  of  chromaffin  cells. 
Such  an  hypothesis  would  account  for  the  increase  in  volume  of 
the  cortex  and  for  the  apparent  increase  in  the  activity  of  the 
specific  cells  of  the  medulla. 

For  the  purely  clinical  part  of  the  work  we  have  selected  the 
first  seven  cases  with  a  persistent  indicanuria  who  have  presented 
themselves.  Their  ages  ranged  from  thirty  to  sixty-five  years. 
In  no  case  was  the  blood  pressure  over  150  Hg.,  and  this  latter 
reading  was  obtained  from  the  oldest  patient  in  the  group.  Ac- 
cordingly, none  of  our  seven  cases  shovv^ed  an  abnormally  high 
presure,  so  that  none  of  them  can  be  placed  in  Huchard's  pre- 
sclerosis class.  It  may  then  be  fair  to  state,  as  far  as  our  small 
material  permits,  that  indicanuria  is  not  synonymous  with  pre- 
sclerosis, and  that  indican,  in  and  of  itself,  does  not  cause  an  ab- 
normally high  pressure.  Whether  this  would  be  so  in  the  presence 
a  renal  insufficiency,  or  whether  indican  can  cause  changes  which 
then  result  in  the  condtion  called  presclerosis,  we  do  not  know. 

As  regards  the  blood  pressure  in  relation  to  the  intensity  of 
the  indicanuria: — In  two  cases,  which  we  were  able  to  follow  a 
long  time,  the  pressure  gradually  fell  as  the  indican  disappeared 


222  DANDRIDGE    MEMORIAL 

from  the  urine.  The  first  case,  a  man  of  sixty,  started  with  a 
pressure  of  150  mm.  Hg.  on  April  10,  1911,  which  on  June  1, 
1911,  when  the  indican  reaction  had  disappeared,  was  134  mm. 
Hg.  On  April  15,  1911,  when  the  test  for  indican  was  very 
marked  the  pressure  was  150  mm.,  but  on  May  15,  when  the 
reaction  was  still  fairly  strong,  the  pressure  was  down  to  115; 
whereas  it  had  again  risen  to  134  mm.  by  June  1,  when  there  was 
no  indican  in  the  urine.  The  other  patient,  a  man  of  thirty-four 
years,  started  with  a  pressure  of  123  mm.  on  March  21,  1911, 
which  fell  to  103  mm.  by  June  12,  1911 ;  the  indican  during  this 
period  gradually  disappeared.  A  third  man,  of  fifty-five  years, 
with  an  initial  pressure  on  May  23,  1911,  of  143  mm.,  in  whose 
urine  the  indican  reaction  did  not  diminish,  had  the  same  pressure 
on  June  13,  1911. 

CONCLUSIONS. 

No  definite  conclusions  are  justified  by  the  work  here  reported, 
but  we  may  say  that  we  have  some  evidence  that  certain  sub- 
stances (indol  and  ty rosin)  have  a  slight  effect  upon  the  adrenal 
glands  and  that  these  glands  are  more  markedly  afifected  than 
the  liver  and  kidneys.  We  have  found  no  evidence  in  our  very 
meager  material  to  support  the  belief  that  indicanuria  is  in  any 
way  responsible  for  the  symptom-complex  named  "presclerosis" 
by  Huchard.  We  do  not  wish  to  give  the  impression,  however, 
that  we  believe  that  the  group  of  bodies,  of  which  indol  is  one, 
does  not  cause  symptoms  in  man.  We  believe  that  symptoms  are 
produced  when  these  bodies  are  present  in  sufficient  concentra- 
tion. We  would  like  to  suggest  that  "sufficient  concentration" 
does  not  depend  upon  rate  of  production ;  in  other  w^ords,  that 
there  is  probably  never  sufificient  indol  produced  in  the  intestine  to 
cause  symptoms  so  long  as  the  oxidative  and  eliminative  func- 
tions are  normal.  Certainly  by  no  means  are  all  persons  with 
persistent  indicanuria  sufferers  from  intestinal  autointoxication. 
It  is  equally  true  that  there  is  a  group  of  individuals  with  per- 
sistent indicanuria  whose  symptpms  are  relieved  when  the  in- 
dicanuria disappears.  These  persons  are  sick,  not  because  too 
much  indol  is  being  formed,  but  because  it  is  not  removed  with 
sufficient  rapidity. 


NEW  BURGH  AND  W  O  O  L  L  E  Y  223 

In  support  of  this  view  we  quote  from  Herter:  "It  may  be  re- 
garded as  settled  that  the  liver,  muscles,  intestinal  epithelium 
(and  other  cells)  normally  exert  a  protective  action  to  the  ner- 
vous system  in  screening  it  from  the  effects  of  an  injurious  per- 
centage of  indol  in  the  blood,  by  the  ability  of  these  structures 
to  quickly  bind  any  indol  which  comes  to  them.  It  may,  more- 
over, be  regarded  as  established  that  the  same  dose  of  indol  ad- 
ministered to  two  human  beings  of  about  equal  weight  may  reg- 
ularly give  rise  to  more  pronounced  nervous  manifestations  in 
one  than  in  the  other.  While  these  inequalities  may  be  partly 
due  to  differences  in  the  rapidity  of  absorption,  no  striking  dif- 
ferences due  to  this  factor  were  noticeable  in  the  excretion  of 
indican  in  the  urine,  and  it  appears  more  probable  that  the  dif- 
ferences in  the  observed  toxic  effects  were  dependent  on  in- 
equalities in  dift'erent  persons  in  respect  to  their  ability  to  oxidize 
indol  and  to  pair  it  with  sulphuric  acid." 

Experiments  performed  by  A.  N.  Richards  and  J.  Howland 
show  the  effect  of  imperfect  oxidation  on  the  fate  of  indol-  To 
reduce  the  oxidizing  processes  in  the  cells,  animals  were  poi- 
soned with  hydrocyanic  acid.  "Rats,  mice,  guinea-pigs  and  dogs, 
subjected  to  subcutaneous  injections  of  potassium  cyanide  too 
small  in  themselves  to  cause  marked  symptoms,  were  later  sub- 
jected to  .  .  injections  of  indol.  The  result  almost  regularly 
observed  was  that  the  convulsive  twitching  which  is  character- 
istic of  the  action  of  phenol  and  of  indol  was  of  greater  inten- 
sity and  longer  duration  in  the  animals  subjected  to  potassium 
cyanide  than  in  the  control  animals." 

REFERENCES. 

Herter:  Bacterial  Infections  of  the  Digestive  Tract.  New  York,  1907. 
The  Macmillan  Co. 

Forchheimer:  Chronic  Intestinal  Autointoxication.  American  Jour. 
:Med.  Sc,  1907.  July. 

Huchard :  The  Diseases  of  the  Heart  and  Their  Treatment,  1909. 

Woolley  and  Newburgh :  Journal  A.  M.  A.,  1911,  Ivi,  1796. 

V.  Fiirth :  Quoted  bv  Adami. 

Adami :  Principles  of  Pathology,  1910,  vol.  i,  p.  670. 

Richards  and  Howland :  Quoted  by  Herter. 


CONTRIBUTIONS  TO  A  COLLOID-CHEMICAL  ANALY- 
SIS OF  ABSORPTION  AND  SECRETION.* 


MARTIN   H.  FISCHER,  M.D. 
I. 

For  a  number  of  years  past  both  theoretical  and  experimental 
evidence  has  been  accumulating  which  would  make  the  colloids 
of  the  cells  and  changes  in  their  state  the  chief  factor  responsible 
for  the  amount  and  variations  in  the  amount  of  water  held  by  the 
cell.  Such  a  conclusion  stands  in  sharp  contrast  to  that  which 
has  been  more  generally  held,  according  to  which  but  small  im- 
portance, or  none,  has  been  assigned  to  the  colloids  in  this  matter. 
The  latter  view  gained  its  main  support  from  the  fact  that  since 
the  first  osmotic  investigations  of  Hugo  de  Vries  and  W.  Pfef- 
fer,  both  animal  and  plant  physiologists  have  very  generally 
adopted  the  view  that  living  cells  represent  osmotic  systems  simi- 
lar in  general  construction  to  the  osmotic  cells  of  our  physico- 
chemical  laboratories ;  and  as  in  these  osmotic  cells  of  our  labora- 
tories pure  colloids  show  practically  no  osmotic  pressure,  it  was 
reasoned  that  they  could  also  show  no  osmotic  pressure  in  the 
living,  supposedly  osmotic,  systems  of  the  biological  worker. 

The  serious  objections  that  can  be  lodged  against  the  osmotic 
conception  of  water  absorption  by  cells,  even  as  modified  by  the 
excellent  researches  of  the  past  fifteen  years,  are  familiar  to 
everyone.  It  was  in  an  attempt  to  account  for  some  of  the  most 
notable  of  these  objections  that  the  role  of  the  colloids  in  the 
general  problem  was  again  considered.  These  studies  showed 
that  variations  in  the  water  content  of  various  cells  are  easily 
explained  not  only  from  a  quantitative  but  also  from  a  qualita- 
tive standpoint  on  the  basis  of  their  colloidal  constitution,  for  the 
variations  that  are  observed  in  cells  when  subjected  to  diflferent 
external  surroundings  are  identical  with  those  which  can  be  in- 
duced in  dififerent  emulsion  colloids  when  subjected  to  the  same 

*  Reprinted  with  additions  from  Kolloidchemische  Beihefte,  ii,  304, 
1911. 

225 


226  DANDRIDGE    MEMORIAL 

external  conditions.  In  this  manner  it  was  found  possible  to 
explain  without  recourse  to  any  belief  in  the  osmotic  constitution 
of  the  living  cell  all  the  phenomena  that  had  previously  been 
explained  on  this  basis,  as  well  as  the  notable  exceptions  which 
biological  workers  were  agreed  could  not  be  so  explained.  And 
hence  the  conclusion  that  the  colloids  of  the  tissues  and  changes 
in  their  state  are  chiefly  responsible  for  the  variations  in  zuater 
content,  that  cJiaracterize  the  living  cell. 

The  question  that  next  presented  itself  was  whether  the  facts 
accumulated  from  study  of  isolated  cells  could  be  utilized  to  ex- 
plain the  special  problems  of  absorption  and  secretion  as  we  ob- 
serve them  in  any  of  the  higher  animals. 

The  absorption  and  secretion  of  water  by  a  multi-cellular  or- 
ganism seems  at  first  sight  to  be  decidedly  different  from  the  ab- 
sorption and  secretion  of  water  as  observed  in  a  single  cell — say 
an  ameba  or  a  muscle  cell.  It  is  an  easy  matter  to  think  of  an 
ameba  as  a  spherical  mass  of  colloidal  material  saturated  with 
water,  and  under  changes  in  its  physico-chemical  surroundings 
or  through  direct  changes  in  its  own  chemical  composition  so 
altering  this  colloidal  material  as  to  make  it  take  up  or  give  off 
water.  As  I  view  it,  this  simple  conception  does  as  a  matter  of 
fact  constitute  the  heart  of  the  entire  problem  of  water  absorp- 
tion and  secretion  as  observed  in  this  animal. 

But  in  a  multicellular  organism  biological  facts  confront  us 
which  do  not  at  first  seem  to  be  interpretable  on  any  such  simple 
basis  as  that  outlined  for  the  ameba.  In  the  mammal,  for  ex- 
ample, we  find  whole  organs  set  apart,  seemingly  endowed  with 
powers  of  absorption  only  while  others  functionate  seemingly 
only  as  secretory  organs.  It  becomes  hard,  for  example,  to  see 
:  just  what  relationship  exists  between  a  mucosal  cell  of  the  small 
intestine  concerned  almost  exclusively  with  an  absorption  of 
water  from  the  lumen  of  the  gut,  or  a  kidney  cell  concerned 
equally  exclusively  with  a  secretion  of  urine,  and  the  ameba  or 
muscle  cell  which  now  absorbs  and  now  secretes  water  either  in 
response  to  its  own  physiological  demands  or  under  the  condi- 
tions with  which  experimentally  we  are  pleased  to  surround  it. 
And  yet  on  closer  analysis  the  difference  between  the  two  is  not 
so  striking.    First  of  all,  we  appreciate  the  fact  that  the  mucosal 


FISCHER  227 

cell  is  an  absorbing  cell  only  so  long  as  we  look  at  it  from  the 
side  of  the  lumen  of  the  gut.  If  we  regard  it  from  the  blood 
vessel  side,  the  mucosal  cell  is  a  secreting  cell,  for  what  it  ab- 
sorbs from  the  gut  it  gives  up  to  the  blood.  Similarly,  the  kidney 
cell  is  a  secreting  cell  only  because  we  usually  look  at  it  from  the 
point  of  view  of  being  a  producer  of  urine — as  a  matter  of  fact, 
everything  that  goes  to  make  up  the  normal  urine  was  absorbed 
from  the  blood.  But  even  if  we  look  at  the  matter  from  the  nar- 
rower point  of  view,  the  intestinal  cells  under  certain  circum- 
stances become  secreting  cells  in  that  they  secrete  substances  into 
the  lumen  of  the  intestine;  and  according  to  the  judgment  of 
some  authors,  certain  kidney  cells  may  reabsorb  materials  that 
have  been  secreted  by  others.  In  essence,  therefore,  secretion  and 
absorption  in  the  higher  animals  is  not  different  from  absorption 
and  secretion  as  observed  in  an  ameba  or  any  isolated  tissue  cell. 
That  which  remains,  therefore,  to  characterize  absorption  and 
secretion  in  the  higher  animals  is  merely  this,  that  under  normal 
circumstances  and  viewed  from  the  point  of  view  of  the  organism 
as  a  whole,  absorption  and  secretion  occur  predominantly  in  one 
direction.  What  requires  special  analysis  in  the  higher  animals 
is,  therefore,  n6t  absorption  and  secretion  per  se,  but  the  condi- 
tions existing  in  the  multicellular  organism  which  make  it  pos- 
sible for  certain  organs  to  act  chiefly  as  absorbing  systems,  while 
others  act  predominantly  in  secreting  systems.  This  is  what  cre- 
ates all  the  problems  that  are  conveniently  grouped  under  the 
general  heading  of  the  special  physiology  of  absorption  and  se- 
cretion, as  observed  in  the  higher  animals. 

Let  us  see,  first  of  all,  if  we  cannot  define  in  general  terms 
what  must  be  the  conditions  which  lie  at  the  bottom  of  the  pre- 
dominant functioning  of  certain  cells  and  tissues  in  one  direction, 
and  this  on  the  basis  of  our  belief  that  the  colloidal  constitution 
of  the  living  cell  is  primarily  responsible  for  the  phenomena  of 
water  absorption  and  secretion  by  the  cell. 

An  ameba  or  an  isolated  cell  or  tissue  derived  from  a  higher 
animal  and  kept  in  a  solution  of  any  kind  is  surrounded  by  this 
solution  on  all  sides.  Could  we  imagine  the  chemical  processes 
within  these  cells  held  in  abeyance,  then  we  can  see  how  these 
cells  would  after  a  time  succeed  in  getting  into  a  state  of  equilib- 


228  DANDRIDGE   MEMORIAL 

rium  with  their  surroundings.  When  such  an  equilibrium  has 
been  estabHshed,  the  cells  neither  absorb  nor  secrete  water.  Only 
as  this  equilibrium  is  disturbed,  either  through  changes  in  the 
surroundings  of  these  cells  or  through  the  specific  chemical 
changes  occurring  in  the  cells,  can  we  expect  a  renewed  absorp- 
tion or  secretion. 

Under  quite  different  conditions  do  we  find  the  individual  cells 
of  the  multicellular  organism  existing  in  the  intact  living  body. 
While  in  a  certain  sense  the  internal  activities  of  the  ameba  may 
be  compared  with  those  of  the  individual  cells  making  up,  say  the 
intestinal  mucosa,  and  there  exists  a  certain  analogy  between  the 
fact  that  both  are  surrounded  by  a  liquid  medium,  here  the  anal- 
ogy stops.  For  while  the  ameba  is  surrounded  on  all  sides  by  the 
same  liquid  medium,  the  cells  of  any  of  the  absorptive  or  secret- 
tory  organs,  found  for  instance  in  a  mammal,  are  through  dif- 
ferent portions  of  their  cell  protoplasm  in  contact  with  entirely 
different  media.  The  cells  constituting  the  intestinal  mucous 
membrane,  for  example,  are  bathed  on  one  side  by  intestinal  con- 
tents ;  on  the  other  by  blood  or  lymph,  or  both  together.  Such 
cells,  like  any  other  absorptive  or  secretory  cells  similarly  situ- 
ated, find  themselves  therefore,  in  the  predicament  of  trying  to 
get  into  equilibrium  with  as  many  different  media  as  surround 
them.  It  is  in  trying  to  do  this  that  all  the  phenomena  that  we 
call  absorption  and  secretion  in  the  higher  animals  are  produced. 

As  I  have  pointed  out  elsewhere,^  it  is  in  the  attempt  to  get 
into  equilibrium  with  the  intestinal  contents  on  the  one  side,  and 
the  blood  on  the  other,  that  the  mucosal  cell  (better,  the  colloidal 
membrane  separating  the  intestinal  contents  from  the  blood),  ab- 
sorbs the  intestinal  contents  and  transfers  them  to  the  blood. 

According  to  my  views,  the  body  of  a  multicellular  organism — 
a  mammal,  for  example — is  built  up  of  a  system  of  emulsion 
colloids  which  in  the  resting  state  are  saturated  with  water.  To 
be  counted  in  with  the  structures  that  make  up  this  water-satu- 
rated colloidal  system  and  composing  an  integral  part  thereof, 
are  the  blood  and  the  lymph.  The  entire  system  will  not  take  up 
any  more  water,  or  give  up  any  except  as  chemical  changes  are 
first  produced  in  it  which  either  increase  or  decrease  the  capacity 
of  the  tissue  colloids  for  water.    We  can  see  how  such  chemical 


FISCHER  229 

changes,  when  occurring  in  a  multicellular  organism,  might  be 
of  such  a  character  as  to  affect  the  constitution  of  the  entire  mass 
of  colloidal  material  that  composes  its  body ;  or  they  might  affect 
only  smaller  parts  of  the  whole.  In  the  former  case  we  should 
get  either  an  absorption  or  a  secretion  of  water  by  the  organism 
as  a  whole,  in  the  latter  we  should  get  only  a  limited  or  localized 
absorption  or  a  secretion  of  water  by  the  parts  involved.  Under 
the  latter  circumstances,  yet  another  thing  is  possible.  Chemical 
changes  might  be  going  on  in  one  part  which  were  leading  to  an 
absorption  of  water,  while  other  changes  were  going  on  in  an- 
other part  which  were  leading  to  a  secretion  of  water.  On  this 
basis  I  have  tried  to  show  how  conditions  are  so  arranged  in  the 
body  as  to  favor  almost  constantly  the  absorption  of  water  from 
the  gastro-intestinal  tract,  while  at  the  same  time  they  favor  the 
secretion  of  the  urine  from  the  kidneys. 

The  following  pages  form  a  continuation  of  this  study  of  ab- 
sorption and  secretion  in  the  higher  animals,  and  deal  particularly 
with  the  problem  of  absorption  from  the  peritoneal  cavity.  They 
represent  an  attempt  to  interpret  this  problem  also  in  the  light  of 
our  colloidal  conceptions  of  water  absorption.  The  conclusions 
drawn  are  based  in  part  on  my  own  experiments,  in  part  on  the 
experiments  of  the  numerous  investigators  who  have  worked  in 
this  field,  but  who  have  interpreted  their  findings  differently  from 
the  way  in  which  I  have  taken  the  liberty  of  doing. 

In  view  of  the  excellent  running  accounts  of  absorption  that 
may  be  found  by  consulting  R.  Heidenhain,^  E.  Waymouth  Reid,* 
Ernest  H.  Starling,^  H.  J.  Hamburger,^  E.  Overton,^  Otto  Cohn- 
heim,^  or  Rudolph  Hober,^  it  is  needless  to  attempt  any  detailed 
definition  of  the  present  status  of  our  knowledge  of  absorption. 
This  is  shown  in  a  masterly  way  by  these  authors.  Depending 
upon  whom  we  consult  we  find  suggested,  as  the  forces  active  in 
this  matter,  variations  in  hydrostatic  pressure,  filtration,  or  the 
two  combined;  diffusion  and  osmotic  pressure,  with  modifica- 
tions of  both  as  determined  by  different  media,  different  mem- 
branes and  different  solutions ;  imbibition ;  and  when  these  physi- 
cal forces  are  found  wanting,  then  the  "peculiar"  forces  of  living 
matter  are  called  upon  for  help.  How  unsatisfactory  are  these 
explanations  is  clearly  enough  evidenced  by  the  divergence  of 


230  DAN  BRIDGE   MEMORIAL 

scientific  opinion  and  the  mutual  criticism  that  finds  expression 
in  the  individual  writings  of  these  authors,  and  this  in  spite  of 
the  fact  that  the  experimental  grounds  upon  which  they  base 
their  opinions  agree  very  well  with  each  other. 

My  own  experiments  that  are  referred  to  below  were  extremely 
simple  in  character,  made  purposely  so  in  order  to  eliminate  the 
many  and  great  errors  that  creep  into  these  absorption  experi- 
ments, as  soon  as  anesthetics,  operations,  animal  boards  and  elab- 
orate pieces  of  apparatus  are  employed.  Had  it  not  been  for  the 
use  of  these,  one  might  have  contented  himself  with  mere  inter- 
pretation of  the  experimental  facts  already  found  by  previous  au- 
thors. How  some  of  these  procedures  affect  absorption  will  be 
pointed  out  at  the  proper  place. 

I  used  healthy  guinea  pigs  which  were  kept  on  a  liberal  diet 
of  timothy  hay,  corn  and  oats,  with  water  ad  libitum.  In  order 
to  permit  comparison  with  each  other  the  animals  in  each  set  of 
experiments  were  taken  from  the  same  cage  and  treated  exactly 
alike.  No  anesthetic  being  necessary,  none  was  given.  The  var- 
ious solutions  and  the  water,  after  warming  to  38°  C,  were  in- 
jected into  the  peritoneal  cavity  by  means  of  a  hypodermic  needle. 
The  animals  were  held  only  during  the  few  moments  necessary 
for  the  injection,  after  which  they  were  allowed  to  run  about 
in  their  cages.  At  the  end  of  a  specified  time  they  were  killed  by 
a  blow  on  the  head,  immediately  opened,  and  the  unabsorbed 
liquid  contained  in  the  peritoneal  cavity  aspirated,  by  means  of 
a  pump,  into  small  flasks.  The  amount  of  fluid  recovered  was 
then  measured. 

Let  it  be  noted  that  what  is  discussed  primarily  in  these  pages 
is  the  absorption  of  water  from  the  peritoneal  cavity.  A  priori 
no  one  would  be  inclined  to  look  upon  the  absorption  of  any  so- 
lution as  representing  a  single  process,  and  yet,  in  practice,  this 
is  done  and  has  been  done  constantly.  On  all  sides  we  see  dis- 
cussed the  absorption  of  a  solution  as  such.  The  absorption  of  a 
solution  represents  the  composite  of  the  absorption  of  the  sol- 
vent, and  the  absorption  of  every  individual  substance  dissolved 
in  that  solvent.  Absorption  of  solvent  and  absorption  of  dis- 
solved substance  may  mutually  affect  each  other  (see  below),  but 
this  does  not  make  them  identical,  nor  does  it  make  the  absorption 


FISCHER  231 

of  the  solution  a  single  process.  Excellent  experimenters  have 
gone  so  far  as  to  look  upon  the  distribution  of  a  dissolved  sub- 
stance (such  as  a  dye)  in  a  tissue  as  evidence  for  the  fact  that 
the  solvent  in  which  that  substance  was  originally  dissolved  was 
present  there,  or  at  Icc.st  had  passed  that  way.  This  is  a  most 
serious  mistake. 

11. 
1.  When  any  liquid  is  injected  into  the  peritoneal  cavity  and 
we  find  that  after  a  time  this  has  been  absorbed,  we  know  from 
anatomical  considerations  that  this  must  have  passed  into  the 
lymph  and  the  blood  streams  after  having  traversed  the  cells  and 
intercellular  substances  which  originally  separated  these  two  cir- 
culating fluids  from  the  liquid  that  was  injected.  If  we  try  to 
formulate  the  problem  in  terms  of  physical  chemistry,  then  our 
purpose  is  to  discover  how  the  absorption  of  a  solution  that  has 
any  composition  we  may  choose  to  give  it,  is  accomplished  by  two 
colloidal  circulating  liquids  (which,  for  the  sake  of  brevity,  we 
will  regard  as  sols)  that  are  separated  from  this  solution  by  a 
solid  colloidal  membrane  (a  gel).  It  is  of  interest  for  our  fur- 
ther discussion  to  first  call  to  mind  which  of  these  two  liquid 
colloids  plays  the  more  important  role  in  this  absorption.  Inas- 
much as  the  peritoneal  cavity  is  usually  regarded  as  an  immense 
lymph  space,  one  might  on  a  priori  grounds  be  inclined  to  look 
upon  the  lymphatic  circulation  as  that  chiefly  concerned  in  the 
problem  of  absorption  from  this  cavity.  And  yet  that  the  lymph 
plays  a  subordinate  part  and  the  blood  circulation  the  chief  role 
is  indicated  not  only  by  E.  H.  Starling  and  Tubby's  ^*'  finding 
that  dyes  appear  in  the  urine  after  injection  into  the  peritoneal 
cavity  before  the  lymph  coming  from  the  thoracic  duct  shows 
any  color,  but  also  by  the  finding  of  Orlow^^  who  noticed  no  in- 
crease in  lymph  flow  after  intraperitoneal  injections  of  salt  so- 
lution, and  that  of  H.  J.  Hamburger^-  who  found  peritoneal  ab- 
sorption unimpaired  after  ligation  of  the  thoracic  duct. 

But,  after  the  point  is  established  that  absorption  from  the 
peritoneal  cavity  is  brought  about  chiefly  through  the  agency  of 
the  blood,  we  have  yet  to  say  why  this  is  the  case.  It  is  evident 
that  the  answer  to  this  question  bears  both  a  quantitative  and  a 
qualitative  element.     In  the  higher  animals  the  lymph  circulation 


232  DANDRIDGE   MEMORIAL 

stands  quantitatively  far  behind  the  circulation  of  the  blood. 
Other  things  being  equal,  the  blood  would  therefore  absorb  more 
than  the  lymph  in  proportion  as  the  blood  flow  through  a  part  ex- 
ceeds quantitatively  the  lymph  circulation  through  the  same  part. 
But  chemical  differences  between  the  two  play,  to  my  mind,  an 
equally  important  part.  The  total  colloid  content  of  the  blood  is 
higher  than  that  of  the  lymph.^^  But,  beyond  this,  the  blood  suf- 
fers rapid  temporary  changes  in  chemical  composition  that  the 
lymph*  does  not  suffer.^*  Chief  among  these  are  the  quantitative 
variations  in  the  content  of  oxygen  and  (especially)  of  the  carbon 
dioxide  as  induced  through  respiration.  Further  changes  in  the 
composition  of  the  blood  are  wrought  through  the  diffusion  of 
metabolic  products  into  and  out  of  it,  when  the  blood  passes 
through  the  kidneys,  active  muscles,  the  liver,  etc.  While  some- 
what similar  changes  are  induced  in  the  lymph  when  this  passes 
through  various  organs,  the  rapid  variations  that  we  find  in  the 
blood  are  for  obvious  reasons  lacking.  But  these  more  marked 
and  rapid  changes  in  the  blood,  combined  with  its  more  rapid  cir- 
culation, mean  at  the  same  time  more  marked  and  rapid  chai;ges  in 
the  surroundings  of  the  various  tissue  cells  about  which  this  cir- 
culating medium  passes.  The  equilibrium  with  their  surround- 
ings which  these  cells  endeavor  to  establish  is  therefore  continu- 
ally being  disturbed  because  of  these  changes  in  their  surro'.-nd- 
dings ;  and,  so  long  as  this  happens,  so  long  must  the  cells  absorb 
or  secrete.  And  hence  the  more  important  function  of  the  blood 
circulation  over  that  of  the  lymph  circulation  is  this  problem  of 
absorption  in  the  higher  animals. 

2.  Let  us  now  turn  to  the  problem  of  the  absorption  of  water 
from  the  peritoneal  cavity.  When  water  is  injected  at  body  temp- 
erature into  the  peritoneal  cavity  of  guinea  pigs  it  is  rapidly  ab- 
sorbed, as  the  following  table  shows : 

^^^^^  ^-  Amount  of  fluid 

Amount  of  water  in  c.c.  recovered 

Guinea  pig              Weight  in  grams              injected  in  c.c.  after  one  hour 

a    413                                 20.8  S.4 

b    535                                20.8  S.4 

c    544                               20.8  4.8 

d    460                               20.8  4.9 

*  Almost  one-fourth  of  the  blood  is  prote  in  Blood  plasma  contains  to 
each  100  parts  almost  9  parts  of  protein;  lymph  contains  3.4  to  4.1  parts. 


FISCHER  233 

There  is  nothing  new  about  this  observation.  Where  we  en- 
counter difficulty  is  in  saying  why  the  water  is  absorbed.  Against 
the  generally  accepted  belief  that  water  is  under  such  circum- 
stances absorbed  because  the  osmotic  pressure  in  the  cells  lining 
the  peritoneum  is  higher  than  that  of  the  distilled  water,  serious 
objections  can  be  raised.  We  know  that  the  peritoneum  does  not 
retain  this  water,  but  gives  it  up  to  the  blood  (chiefly).  On  the 
osmotic  basis  this  secretion  into  the  blood  could  therefore  occur 
only  because  the  blood  had  a  higher  osmotic  concentration  than 
the  cell  contents.  As  a  matter  of  fact  we  know  that  body  cells, 
lymph  and  blood  have,  to  all  intents  and  purposes,  the  same 
osmotic  concentration.  The  still  more  serious  objection  that  this 
osmotic  conception  of  water  absorption  ignores  entirely  the  im- 
portant part  played  by  the  intercellular  substances  need  not  be 
discussed  here.  That  an  injection  of  water  into  the  peritoneum 
makes  the  cells  here  take  up  water  because  of  an  increased  hydro- 
static pressure  directly  induced  by  the  injection,  or  aided  by 
the  contractions  of  the  abdominal  muscles,  etc.,  is  also  scarcely 
tenable.  The  injection,  first  of  all,  does  not  appreciably  increase 
the  intra-abdominal  pressure;  and  secondly,  absorption  occurs 
when  the  abdomen  is  opened,  or  in  a  dead  animal  (see  below). 

We  have  no  difficulty  in  interpreting  the  absorption  of  water 
from  the  peritoneal  cavity  as  a  colloidal  phenomenon.  In  order 
that  the  absorption  of  zmter  m-ay  occur,  the  emulsion  colloids  of 
the  peritoneum  must  only  he  unsaturated  zmth  zvater.  But  when 
we  consider  the  fact  that  after  a  few  cubic  centimeters  of  water 
have  been  absorbed  from  the  peritoneal  cavity,  more  may  be  ab- 
sorbed and  this  may  be  repeated  almost  without  limit,  then  we 
have  to  conclude  that  under  normal  circumstances  the  tissues  com- 
posing the  peritoneum  are  constantly  unsaturated  zi'ith  water. 
What  we  really  have  to  discuss,  therefore,  are  the  conditinos  that 
combine  to  keep  the  colloids  of  these  tissues  unsaturated  with 
water  in  the  living  animal. 

The  first  of  these  conditions  is  the  continuous  production  of 
acid  (carbon  dioxide)  in  the  tissues  composing  the  peritoneum. 
In  consequence  of  this  acid  production  in  these  tissues  their 
capacity  for  water  is  increased,  and  they  absorb  water  from  any 
available  source.    If  water  is  present  in  the  peritoneal  cavity  they 


234  DANDRIDGE    MEMORIAL 

will  take  it  up.  But  this  would  only  lead  to  a  swelling  of  the 
peritoneal  tissues.  We  wish  to  emphasize  that  by  ''peritoneal 
tissues"  we  mean  cells  plus  intercellular  substance.  As  in  this 
process  an  upper  limit  might  soon  be  reached  and  absorption 
cease,  this  alone  cannot  lead  to  the  continuous  absorption  which 
we  found  to  exist.  Therefore,  we  need  to  introduce  a  second 
variable,  and  this  is  found  in  the  circulation  of  the  blood  and  the 
lymph.  Through  these  the  carbon  dioxide  produced  in  the  cells 
is  constantly  being  carried  away.  But  to  carry  this  away  from 
the  tissues  is  to  reduce  the  capacity  of  the  colloids  of  the  peri- 
toneum for  water,  which,  in  consequence,  they  now  give  up.  As 
long  as  the  circulation  is  maintained  in  a  normal  way  absorption 
from  the  peritoneal  cavity  must  therefore  be  continuous,  for  zuJtile 
the  tissues  of  the  peritoneum  are  on  tlie  one  side  busy  in  absorbing 
zmter  they  are,  on  the  other,  busy  in  giving  it  up  to  the  blood 
along  with  their  carbon  dioxide. 

What  the  blood  does  with  this  water  is  beyond  the  scope  of 
this  paper  to  discuss,  but  it  may  not  be  out  of  order  to  point  out 
that  it  also  carries  the  water  in  combination  with  the  colloids 
found  in  the  blood.  As  the  arterial  blood,  low  in  carbon  dioxide 
(representing,  as  we  have  said,  a  liquid  colloidal  solution  satu- 
rated with  water),  enters  the  capillaries,  there  diffuses  into  it  the 
carbon  dioxide  that  is  being  produced  in  the  cells.  Through  this 
the  capacity  of  the  blood  colloids  to  hold  water  is  raised,  they  find 
themselves  in  an  unsaturated  condition,  and  so  are  able  to  absorb 
water  from  any  available  source.  This  could  be  water  directly, 
though  in  the  living  body  it  means  that  the  blood  robs  any  tissue 
of  its  water  that  is  holding  it  with  less  avidity  than  that  repre- 
sented by  the  colloids  of  the  blood.  In  the  case  under  discussion 
the  blood  absorbs  water  from  the  tissues  composing  the  perito- 
neum. The  peritoneum,  in  its  turn,  takes  water  from  the  perito- 
neal cavity,  if  any  is  present  there.  The  now  venous  blood,  with 
its  higher  water  content,  passes  to  the  lungs,  where  the  carbon 
dioxide  escapes.  When  this  happens  the  blood  colloids  are  unable 
to  longer  retain  the  water  absorbed  previously,  and  this  becomes 
"free"  in  the  blood.  It  is  this  "free"  water  that  under  normal 
conditions  the  kidney  extracts  from  the  blood,  and,  by  a  process 


FISCHER 


235 


the  reverse  of  that  which  we  have  described  for  peritoneal  ab- 
sorption, secretes  as  urine. ^^ 

3.  The  conclusion  that  only  "free"  water  can  be  secreted  by  the 
kidneys  can  be  supported  in  a  number  of  ways.  Any  method  by 
which  w^e  can  get  "free''  water  into  the  blood  is  a  method  which 
produces  a  proportionate  increase  in  urinary  output.  If  water  is 
introduced  in  a  "bound"  state,  in  other  words,  in  combination  with 
a  colloid,  then  no  secretion  is  obtained^''.  Xow,  since  absorption 
represents  the  mirror  image  of  secretion,  it  ought  to  be  possible 
to  establish  a  similar  series  of  experimental  facts  for  absorption, 
and  so  apply  a  first  test  to  the  ideas  of  peritoneal  absorption  ad- 
vanced above.  If  only  "free"  water  can  be  secreted,  then  "free" 
water  ought  to  prove  itself  most  readily  absorbable ;  and,  since 
colloidal  solutions  cannot  be  secreted  by  the  kidney,  colloidal  so- 
lutions ought  to  prove  themselves  non-absorbable  from  the  perito- 
neal cavity,  except  as  they  first  suffer  changes  in  state  which 
makes  them  liberate  the  water  contained  in  them.  As  the  follow- 
ing experiments  of  Table  II  show,  this  is  the  case: 

Table  II.  Amount  of  fluid 

Weight  Amount  and  character  in  c.c.  recovered 

Guinea  pig        in  grams  of  solution  injected  after  one  hour 

a 533  20.8  c.c.  water  5.4 

b 537  20.8  c.c.  white  of  egg  (natural)           18.4 

c 5^5  31.2  c.c.  water  1  .(> 

d 563  31.2  c.c.  white  of  egg  (natural)          27.7 

Table  III.  Amount  of  fluid 

Weight  Amount  and  character  in  c.c.  recovered 

Guinea  pig        in  grams  of  solution  injected  after  one  hour 

a 417  20.8  c.c.  water  (control)  5.4 

b 397  20.8C.C.  l-12mol.  NaQ  11.8 

c 419  20.8  C.c.  i^     mol.  NaCl  13.0 

d 488  20.8  c.c.  1-6   mol.  NaCl  14.6 

e 445  20.8  c.c.  14     mol.  NaCl  19.9 

4.  The  theoretical  interpretations  of  the  findings  of  Table  III 
are  about  os  follows  : 

When,  in  place  of  the  pure  water,  a  sodium  chloride  solution  is 
introduced  intraperitoneally  we  may  assume  that  the  water  of 
this  solution  tries  to  diffuse  into  the  cells  just  as  though  the  salt 
were  not  there.  But,  at  the  same  time  that  this  is  occurring,  the 
salt  is  also  diffusing  into  the  peritoneum.  Just  w^hy  this  happens 
is  discussed  below.  But  the  presence  of  this  salt  in  the  colloids 
of  the  peritoneal  tissues  will  make  these  tend  to  give  up  their 


236  DANDRIDGE   MEMORIAL 

water.  The  salts  will,  therefore,  tend  to  counteract  the  effect  of 
the  carbon  dioxide  in  the  cells.  The  normal  fall  which  tends  to 
make  the  water  move  from  the  peritoneal  side  of  the  peritoneal 
absorbing  membrane  to  the  vascular  side  will  now  be  counteracted 
by  one  occurring  in  the  opposite  direction.  The  normal  streaming 
of  water  which  tends  to  make  for  an  absorption  from  the  perito- 
neum will  be  met  by  a  counterstream  which  tends  to  make  for  a 
secretion  from  this  structure.  The  end  result,  so  far  as  absorp- 
tion is  concerned,  will  represent  the  algebraic  sum  of  the  two. 
If  this  second  stream  is  not  a  great  one  there  will  be  only  a  slight 
reduction  in  the  rapidity  with  which  the  water  is  absorbed.  This 
is  what  happens  with  the  dilute  salt  solution.  But,  as  the  concen- 
tration of  the  salt  increases,  this  counter  current  must  become 
more  and  more  manifest,  so  tl[iat,  as  in  the  last  experiment  (e) 
given  in  Table  III,  practically  no  absorption  (of  water)  occurs 
within  the  time  limits  set  for  the  experiment. 

5.  In  equimolecular  concentrations  different  salts  affect  to  very 
unequal  degrees  the  absorption  of  water  by  colloids  swelling  in 
the  presence  of  an  acid.  So  also,  and  in  the  same  general  order, 
do  they  affect  the  absorption  of  water  by  the  peritoneum. 

Ta^^^  IV.  Amount  of  fluid 

Weight  Amount  and  character                     in  c.c.  recovered 

Guinea  pig        in  grams  of  solution  injected                        after  one  hour 

a 643  20.8  c.c.  ^  mol.  sodium  chloride            7.0 

b 594  20.8  c.c.  Ys  mol.  sodium  acetate            10.0 

c 551  20.8  c.c.  %  mol.  sodium  nitrate             12.6 

d 409  20.8  c.c.  %  mol.  sodium  sulphate         20.0 

e 496  20.8  c.c.  Ys  mol.  sodium  citrate             23.4 

f 492  20.8  c.c.  %  mol  disodium  phosphate   25.6 

Table  V.  Amount  of  fluid 

Weight        Amount  and  character  in  c.c.  recovered 

Guinea  pig        in  grams  of  solution  injected  after  one  hour 

a 343  20.8  c.c.  J/^  mol.  potassium  iodide  3.4 

b 335  20.8  c.c.  %  mol.  potassium  bromide       8.8 

c 322  20.8  c.c.  J/^  mol.  potassium  chloride     11.0 

d 290  20.8  c.c.  3^  mol.  potassium  sulpho-      13.4 

cyanate 

e 355  20.8  c.c.  J^  mol.  potassium  nitrate        13.4 

f 354  20.8  c.c.  %  mol.  potassium  acetate        16.8 

g 363  20.8  c.c.  ^  mol.  potassium  tar-  18.9 

trate  (died  40  minutes 

after  injection) 
h 386  20.8  c.c.  J/^  mol.  potassium  citrate        20.5 

(died  15  minutes  after 

injection) 


FISCHER  237 

Table  VI.  Amount  of  fluid 

Weight  Amount  and  character                     in  c.c.  recovered 

Guinea  pig        in  grams  of  solution  injected                        after  one  hour 

a 452  20.8  c.c.  J^  mol.  potassium  chloride     12.8 

b 396  20.8  c.c.  J^  mol.  ammonium  chloride    13.7 

c 484  20.8  c.c.  J^  mol.  magnesium  chloride    19.4 

d 476  20.8  c.c.  J^  mol.  calcium  chloride        24.2 

e 502  20.8  c.c.  ^  mol.  strontium  chloride      24.4 

As  Tables  IV,  V  and  VI  show  very  clearly,  every  one  of  the 
salts  employed  markedly  retards  the  absorption  of  water  from 
the  peritoneal  cavity.  This  harmonizes  entirely  with  the  fact  that 
the  presence  of  every  salt  inhibits  the  absorption  of  water  by  such 
an  emulsion  colloid  as  fibrin,  gelatine  or  serum  albumin  which  is 
swelHng  in  the  presence  of  an  acid.  But  the  parallelism  between 
the  two  processes  is  much  closer  than  this.  We  note  in  Table  IV, 
for  example,  where  the  effects  of  equimolecular  solutions  of 
sodium  salts  are  compared,  that  the  sulphate,  citrate  and  phos- 
phate have  an  effect  far  above  that  of  the  chloride,  acetate  or 
nitrate  in  preventing  absorption.  In  Table  V,  where  the  effects 
of  a  series  of  potassium  salts  are  compared,  the  order  of  the 
anions  is  again  the  familiar  one  observed  in  studies  on  pure 
colloids.  Table  VI  brings  out  the  same  fact  for  a  series  of  dif- 
ferent kations.  That  the  results  should  be  so  nearly  identical 
with  the  effects  of  various  salts  on  pure  colloids  is  really  some- 
what surprising  when  we  remember  that  in  such  experiments  as 
these  one  is  compelled  to  w^ork  with  a  very  considerable  experi- 
mental error,  arising  from  the  fact  that  in  each  of  these  series  of 
experiments  several  animals  are  used,  that  we  cannot  control  the 
amount  of  water  consumed  by  the  animals  just  before  being  used, 
that  we  cannot  escape  the  specific  poisonous  effects  exerted  by  the 
different  salts  employed,  etc.  Nevertheless  the  experimental  re- 
sults are  point  for  point  almost  identical  with  the  findings  on  pure 
colloids.  This  indicates  to  my  mind  how  predominant  is  the  col- 
loidal element  in  this  problem  of  absorption. 

6.  As  compared  with  the  effect  of  electrolytes,  various  non- 
electrol)les  affect  the  absorption  of  water  by  colloids  in  the  pres- 
ence of  any  acid  only  slightly.  The  following  gives  the  results 
obtained  w^hen  solutions  of  various  non-electrolytes  in  concentra- 
tions osmotically  about  equivalent  to  the  solutions  of  the  various 
salts  used  above,  were  injected  intraperitoneally : 


238  DANDRIDGE    MEMORIAL 

T^^^"V"-  Amount  of  fluid 

Weight  Amount  and  character  in  c.c.  recovered 

Guinea  pig        in  grams  of  solution  injected  after  one  hour 

a 425  20.8  c.c.  14  mol.  ethyl  alcohol  5  8 

b 434  20.8  c.c.  J4  mol.  methyl  alcohol  2.1 

c 464  20.8  c.c.  water  (control)  5.6 

d 583  20.8  c.c.  ^  mol.  urea  11.7 

e 569  20.8  c.c.  14  mol.  glycerine  18.2 

f 687  20.8  c.c.  14  mol.  glycerine  17.4 

g" 521  20.8  c.c.  J4  t^o\.  cane  sugar  25.7 

h 725  20.8  c.c.  ^  mol.  cane  sugar  27.0 

i 522  20.8  c.c.  %  mol.  dextrose  26.3 

j 710  20.8  c.c.  ^  mol.  dextrose  29.0 

It  is  clear  from  this  table  that  ethyl  and  methyl  alcohols  do  not 
delay  the  absorption  of  water  from  the  peritoneal  cavity.  On  the 
other  hand,  urea,  glycerine  and  the  two  sugars  used,  produce  a 
very  decided  inhibition.  The  sugars  even  produce  a  secretion  of 
fluid  into  the  peritoneal  cavity  exactly  as  we  found  certain  bi- 
valent and  trivalent  anions  and  kations  to  do  in  Tables  IV  and  VI. 
The  effects  of  ethyl  and  methyl  alcohol  agree  with  the  findings  on 
pure  colloids.  In  the  case  of  glycerine  and  the  sugars  the  effect 
on  the  peritoneum  is  much  more  pronounced  than  would  be  ex- 
pected from  the  action  of  these  compounds  on  fibrin  or  gelatine. 
Just  how  the  result  is  to  be  explained  remains  conjectural.  The 
concentrations  employed  are  rather  high,  and  so  we  have  to  re- 
member the  fact  that  while  non-electrolytes  do  not  markedly 
inhibit  the  absorption  of  water  by  various  colloids  in  low  con- 
centrations, they  do  this  in  the  higher  concentrations.  A  second 
factor  is  that  the  water  is  bound  to  these  non-electrolytes  (glycer- 
ine and  the  sugars)  more  intimately  than  to  the  various  salts.  In 
other  words,  the  water  is  not  "free,"  but  in  a  bound  state  as  in  the 
colloidal  solutions  represented  by  egg  albumin,  blood,  etc.  Finally, 
these  sugar  and  glycerine  solutions  produce  a  degree  of  "irrita- 
tion" of  the  peritoneum  (acid  production  in  the  cells?),  as  evi- 
denced by  a  redness  and  a  slightly  wrinkled  appearance  that  is 
entirely  lacking  when  other  solutions  are  employed. 

7.  Both  alkalies  and  acids  when  injected  intraperitoneally  delay 
the  absorption  of  water,  as  indicated  in  the  following  table: 


FISCHER 


239 


'^•^^"'V"^-  Amount  of  fluid 

Weight  Amount  and  character  in  c.c.  recovered 

Guinea  pig        in  grams  of  solution  injected  after  one  hour 

a 544  20.8  c.c.  water  (control)  4.7 

b 545  20.8  c.c.  0.01  normal  NaOH  6.2 

c 543  20.8  c.c.  0.02  normal  NaOH  11.0 

d 568  20.8  c.c.  0.04  normal  NaOH  10.6 

e 460  20.8  c.c.  water  ( control )  4.8 

f 460  20.8  c.c.  0.01  normal  HCl  7.4 

g 447  20.8  c.c.  0.02  normal  HCl  12.4 

h 450  20.8  c.c.  0.03  normal  HCl  12.0 

Just  how  these  results  are  to  be  interpreted  on  the  colloidal 
basis  remains  at  this  time  somewhat  conjectural.  From  the  con- 
centrations employed  and  the  appearance  of  the  animals  on  post- 
mortem examination  it  has  seemed  to  me  that  both  produce  an 
excessive  swelling  of  the  peritoneal  tissues.  This  excessive  swell- 
ing would  delay  absorption,  not  alone  by  occluding  the  lumina  of 
the  capillaries  supplying  the  peritoneum  and  so  decreasing  the 
absolute  blood  flow  through  these  tissues,  but  by  so  increasing  the 
avidity  of  the  peritoneal  tissues  for  water  that  the  blood  passing 
through  them  is  not  enabled  to  take  the  water  away  from  them 
with  its  usual  ease. 

Tabi-E  IX.  Recovered 

Amount  from  second 

of  fluid       pouring  in 

Amount  and  recovered     of  20.8  c.c. 

Hours      Weight  character  of        in  c.c.  after  water  after 

Guinea  pig      dead      in  grams        solution  injected  1  hour         1  hour 

a just  dead        331  20.8  c.c.  water  7.6 

b just  dead        396  20.8  c.c.  water  9.0 

c 1.00  333  20.8  c.c.  water  9.4  15.3 

d 2.30  351  20.8  c.c.  water  9.3  15.0 

e 7.30  395  20.8  c.c.  water  8.0 

f 24.00  375  20.8  c.c.  water  12.5 

g 48.00  353  20.8  C.C.  water  17.0 

h 0.15  267  20.8  C.C.  i/^  mol.  NaCl     13.2 

i 0.15  295  20.8  c.c.  %  mol.  10.6* 

Na.S04 

j 0.15  299  20.8  c.c.  i/^  mol.  11.4* 

sodium  citrate 
*  A  part  of  the  peritoneal  fluid  was  accidentally  lost. 

8.  The  above  table  shows  how  water  and  various  salt  solutions 
are  absorbed  from  the  peritoneal  cavities  of  dead  animals.  The 
guinea  pigs  were  killed  by  a  blow  on  the  head,  and  injected  sub- 
sequently in  the  same  way  as  in  the  experiments  with  living  ani- 
mals already  detailed  above.    After  the  liquids  were  injected  the 


240  DANDRIDGE   MEMORIAL 

animals  were  turned  about  for  a  few  times  to  allow  the  liquids  to 
spread  through  the  peritoneal  cavity,  and  were  then  laid  quietly 
on  their  bellies  for  one-half  hour,  after  which  they  were  turned 
on  their  backs  for  one-half  hour. 

The  table  shows  that  water  is  readily  absorbed  from  the  perito- 
neal cavities  of  dead  animals.  How  is  the  result  to  be  explained? 
The  answer  is  not  essentially  different  from  that  given  for  the 
living  animal.  An  acid  production  in  the  tissues  is  again  re- 
sponsible for  increasing  the  capacity  of  the  tissue  colloids  to  hold 
water.  Only,  while  we  attributed  this  to  carbonic  acid  in  the 
living  animal,  we  can  attribute  it  in  the  case  of  the  dead  animal 
not  only  to  this  acid  but  in  addition  to  lactic  and  the  other  acids 
that  we  know  are  produced  post  mortem.  The  longer  an  animal 
is  dead,  the  higher  we  may  assume  becomes  the  concentration  of 
the  acids  in  the  various  tissues.  On  this  basis  we  might  expect 
a  progressively  greater  absorption  of  water  with  every  increase  in 
the  length  of  time  that  an  animal  is  dead.  But  this  could  hold 
only  within  certain  limits,  for  in  pure  colloids  we  know  that  with 
a  progressive  increase  in  acid  concentration  the  absorption  of 
water  increases  only  up  to  a  certain  point,  after  which  a  decreased 
absorption  is  noted.  The  same  is  evident  in  Table  IX,  where 
animals  long  dead  (/  and  g),  show  a  decidedly  lower  absorption 
of  water  than  animals  dead  only  a  short  time. 

As  is  sufficiently  well  indicated  by  the  results  obtained  with 
animals  h,  i  and  /  various  salts  retard  the  absorption  of  water 
from  the  peritoneal  cavity  of  dead  animals  as  they  do  in  living 
animals,  and,  we  would  add,  for  the  same  reason. 

III. 

1.  The  foregoing  paragraphs  which  show  that  the  same  condi- 
tions which  retard  the  absorption  of  water  by  such  an  emulsion 
colloid  as  fibrin  or  gelatine,  retard  in  almost  identical  fashion  the 
absorption  of  water  from  the  peritoneal  cavity,  prove,  it  seems  to 
me,  that  the  two  processes  are  in  essence  the  same.  What  is  next 
in  order  is  to  compare  this  process  of  peritoneal  absorption  with 
the  processes  of  absorption  as  observed  in  other  regions  of  the 
mammalian  organism  to  see  if  the  conclusions  drawn  regarding 
absorption  as  observed  in  the  peritoneal  cavity  cannot  be  extended 


FISCHER  241 

to  cover  at  least  some  of  these.  Of  chief  interest  in  this  connec- 
tion, because  of  its  physiological  importance,  is  the  question  of 
absorption  from  the  intestinal  tract. 

To  any  one  conversant  with  the  wealth  of  experimental  data  on 
alimentary  absorption  that  has  been  accumulated  by  Voit  and 
Bauer,^^  R.  Heidenhain,^®  Franz  Hofmeister,^"  H.  J.  Ham- 
burger,-" Rudolph  Hober,-^  G.  B.  Wallace  and  A.  R.  Cushny,^^ 
Otto  Cohnheim,-^  E.  Waymouth  Reid,^*  and  G.  Kovesi,-^  the 
following  are  familiar  facts : 

When  water  is  introduced  into  a  segment  of  intestine  it  is  rap- 
idly absorbed.  All  salt  solutions,  so  far  as  the  water  in  them  is 
concerned,  are  absorbed  less  rapidly  than  in  pure  water.  The 
concentration  of  the  salt  solution  is  an  important  factor  in  this 
phenomenon.  When  sodium  chloride  solutions  of  various  con- 
centrations are  compared,  it  is  found  that  they  are  absorbed  the 
more  slowly  the  higher  the  concentration  of  tr.e  salt.  If  suffi- 
ciently strong  solutions  are  employed  there  mi.y  first  result  a 
pouring  out  of  liquid  into  the  lumen  of  the  gut,  so  that  the  solu- 
tion becomes  diluted,  after  which  it  is  slowly  absorbed. 

When  the  absorption  of  equimolecular  (or  better,  osmotically 
equivalent)  solutions  of  different  salts  is  studied,  it  is  found  that 
these  are  absorbed  at  very  different  rates.  The  effect  of  the  pres- 
ence of  any  salt  in  a  solution  upon  the  absorption  of  water  from 
that  solution  may  be  expressed  as  follows :  With  a  given  base,  the 
anions  arrange  themselves  in  the  following  order,  where  that 
which  retards  the  absorption  of  water  least  is  given  first :  Chloride, 
bromide,  iodide,  nitrate,  sulphate,  phosphate.  With  a  given  acid, 
the  order  of  the  kations  is  as  follows  (R.  Hober),  that  least  ef- 
fective in  preventing  the  absorption  of  water  being  given  first: 
Potassium,  sodium,  calcium,  magnesium,  barium.  It  is  easy  to 
see  that  the  order  of  the  various  salts  is  practically  identical  with 
that  found  above  in  the  experiments  on  peritoneal  absorption. 
The  position  of  the  acetate,  tartrate  and  citrate,  not  given  in  the 
above  ion  lists,  can  be  determined  by  consulting  the  tables  of 
Wallace  and  Cushny,  when  it  is  found  that  these  two  occupy  a 
place  in  the  absorption  of  water  from  the  gut  which  is  the  same 
as  that  occupied  by  them  in  the  case  of  peritoneal  absorption. 
With  any  of  these  salts  as  with  ordinary  NaCl  the  delay  in 


242  DANDRIDGE    MEMORIAL 

the  absorption  of  the  water  grows  in  every  instance  with  the  con- 
centration of  the  salt.  A  point  is  finally  reached  where  such 
water  as  is  introduced  into  the  intestine  is  not  only  not  absorbed, 
but  water  is  secreted  into  the  gastro-intestinal  tract.  This  point 
of  concentration  lies  high  in  the  case  of  sodium  chloride,  sodium 
bromide,  etc.,  but  very  low  in  the  case  of  sodium  sulphate,  phos- 
phate, tartrate,  citrate,  etc.  This  is  one  of  the  chief  reasons  why 
the  last  named  are  known  as  "saline  cathartics."  Point  for  point, 
therefore,  the  absorption  and  secretion  of  water  by  the  perito- 
neum is  identical  with  th2  absorption  and  secretion  of  water  by 
the  gut,  and  both  are  comparable  with  the  absorption  and  the 
secretion  of  water  by  simple  colloids  when  placed  in  like  sur- 
roundings. 

The  identity  of  the  processes  of  absorption  from  the  peritoneal 
cavity  and  from  the  intestinal  lumen  goes  even  further  than  this. 
The  rapid  absorption  of  aqueous  solutions  of  various  alcohols 
from  the  intest'nal  tract  shows  that  these  non-electrolytes  do  not 
interfere  with  the  absorption  of  water  here  even  when  they  are 
present  in  concentrations  osmotically  equivalent  to  those  of  the 
active  salts.  Neither  do  the  alcohols  delay  the  absorption  of 
water  by  the  peritoneum.  Sugar  solutions  and  glycerine,  on  the 
other  hand,  behave  in  the  intestinal  tract  so  far  as  the  absorption 
of  water  from  their  solutions  is  concerned,  as  they  do  when  intro- 
duced intraperitoneally.  The  slow  absorption  of  water,  or,  in 
response  to  a  solution  of  sufficiently  high  concentration,  the 
actual  secretion  of  water  into  the  gut,  is  evidenced  not  only  by 
direct  experiment  but  by  every-day  clinical  experience.  Are  not 
the  sugars,  when  consumed  in  any  considerable  quantities,  cap- 
able of  producing  watery  stools  (independently  of  any  previous 
fermentation  with  the  production  of  organic  acids),  and  do  not 
glycerine  enemas  produce  the  same  secretion  of  water  into  the 
bowel  that  results  when  enemas  containing  any  of  the  saline  ca- 
thartics are  employed? 

Furthermore,  we  have  interesting  parallels  of  experiments 
which  show  that  water  when  united  with  an  emulsion  colloid 
is  incapable  of  being  absorbed  without  first  being  freed.  Protein 
solutions  (such  as  egg  white)  are  practically  not  absorbed  from 
the  intestinal  tract  unless  proteolytic  ferments  are  present  which, 


FISCHER  243 

by  acting  on  the  proteins  chemically,  destroy  their  markedly  emul- 
sion colloid  character,  and  so  liberate  the  water  held  by  them. 
In  this  way  also  can  we  understand  the  behavior  of  cellulose 
and  especially  agar-agar  in  preventing  constipation.  The  com- 
monest cause  of  constipation  resides  in  the  too  perfect  absorp- 
tion of  water  from  the  gastro-intestinal  contents.  It  is  a  time- 
honored  custom  to  suggest  the  addition  of  vegetables  to  the  diet 
of  such  individuals.  In  addition  to  the  action  of  the  salts,  (ci- 
trates, tartrates,  etc.)  obtained  from  vegetables  and  the  effects 
of  the  production  (through  fermentation)  of  certain  organic 
acids  in  the  bowel  which  alone  tend  to  prevent  a  too  great  ab- 
sorption of  water  from  the  gastro-intestinal  contents,  the  high 
cellulose  content  of  such  a  diet  (that  is  to  say  its  high  emulsion 
colloid  content)  makes  it  impossible  for  the  mucosa  to  get  the 
water  out  of  it.  Since  cellulose  is  not  changed  (except  very 
slightly  by  certain  bacteria)  in  its  passage  through  the  gastro- 
intestinal tract,  it  retains  all  the  water  with  which  it  was  saturated 
before  being  consumed,  or  with  which  it  saturates  itself  in  its 
course  through  the  alimentary  tract.  The  same  explanation  holds 
for  agar-agar  or  the  feeding  of  any  of  the  Japanese  sea  weeds 
from  which  this  is  prepared.  Agar-agar  is  a  typical  emulsion 
colloid  which  is  incapable  of  being  affected  chemically  in  its  pas- 
sage through  the  gastro-intestinal  tract  (L.  B.  Mendel  and  Saiki), 
and  so  any  water  that  it  may  have  absorbed  before  being  swal- 
lowed, or  may  absorb  in  the  gastro-intestinal  tract,  is  retained. 
In  this  way  the  inspissation  of  the  gastro-intestinal  contents  (and 
so  the  constipation)  is  prevented. 

2.  Elsewhere,-^  I  have  pointed  out  how  secretion  from  such 
an  organ  as  the  kidney  is  the  mirror  image  of  absorption,  as  it 
occurs  from  the  alimentary  tract,  for  example.  As  a  high  carbon 
dioxide  content  of  the  blood  (venous  blood)  favors  the  absorp- 
tion of  water,  so  only  a  low  content  (arterial  blood)  will  main- 
tain the  secretion  from  the  kidney.  As  water  united  to  emul- 
sion colloids  cannot  be  absorbed,  so  water  united  to  emulsion 
colloids  cannot  be  secreted.  All  the  substances  that  interfere  with 
the  absorption  of  water  from  the  alimentary  tract  favor  the  se- 
cretion of  urine,  those  that  interfere  most  with  the  absorption  of 
water    (saline  cathartics)    being  those  that  induce  the  greatest 


244  DAN  BRIDGE  MEMORIAL 

diuresis  (saline  diuretics)  etc.  The  "selective"  absorption  of 
dissolved  substances  from  the  alimentary  tract  corresponds  with 
a  "selective"  secretion  from  the  kidney.  In  both  cases  this  rep- 
resents an  attempt  to  establish  an  equilibrium  in  the  distribution 
of  each  of  the  dissolved  substances  either  "absorbed"  or  "secre- 
ted" betw^een  the  three  phases  constituting  any  absorptive  or 
secretory  system. 

/  would  now  like  to  point  out  that  the  formation  of  lymph  is 
entirely  analogous  to  the  secretion  of  urine  and  is  governed  by 
similar  laws-  The  "secreting  membrane"  in  this  case  is  found  in 
the  cells  and  the  intercellular  substances  that  separate  the  blood 
capillaries  from  the  lymph  capillaries.  It  is,  of  course,  clear  that 
these  cells  and  their  intercellular  substances  constitute  the  bulk 
of  the  body  tissues.  Anything  that  makes  these  cells  with  their 
intercellular  substances  yield  up  water  increases  lymph  flozi^. 

Let  us  first  call  attention  to  the  fact  that  an  increased  arterial 
circulation  to  a  part  increases  lymph  flow.  A  classic  experiment 
in  this  line  is  the  observation  that  an  increased  lymph  flow  from 
the  neck  is  obtained  when  the  salivary  glands  are  active  (supplied 
with  much  arterial  blood).  Under  such  circumstances  various 
tissues  in  the  neck  are  rapidly  freed  of  their  carbon  dioxide  (and 
other  acids).  This  decreases  the  capacity  of  their  colloids  for 
water,  and  so  they  give  it  up,  in  part  to  the  blood,  in  part  to  the 
lymph. 

All  salt  solutions,  when  injected  into  the  blood  in  sufficiently 
concentrated  solutions,  increase  lymph  flow.  \Mien  sodium  chlor- 
ide, sodium  bromide,  etc.,  are  employed,  these  have  to  be  injected 
in  (osmotically)  stronger  solutions  than  when  sodium  sulphate, 
sodium  phosphate,  etc.  are  used.  The  same  thing  happens  in  ex- 
perimental diuresis.  These  experiments  on  the  formation  of 
lymph  are  easily  explained  by  saying  that  the  salts  diffuse  into 
the  tissues  and  make  these  give  up  their  water  which  then  passes 
in  part  into  the  blood,  but  in  part  again,  into  the  lymphatics.  A 
similar  explanation  can  be  given  of  the  "lymphogogue"  action  of 
various  sugars.  Physostigmine  and  pilocarpine  increase  lymph 
flow ;  atropine  and  morphine  decrease  it.  In  the  doses  ordin- 
arily used,  the  former  makes  in  toto  for  an  increased  supply  of 
oxygen  and  the  more  rapid  removal  of  carbon  dioxide  from  the 


FISCHER  245 

cells,  the  latter  for  a  decreased  one.  While  the  former  means  a 
decrease  in  the  capacity  of  the  tissue  colloids  to  hold  water,  the 
latter  means  an  increase;  these  in  turn  mean  a  giving  up  of  fluid 
to  the  lymph  in  the  first  case,  and  none  available  for  such  a  pur- 
pose in  the  second- 

3.  In  this  connection  a  word  may  not  be  amiss  in  calling 
attention  to  the  useful  purpose  served  by  the  vasomotor  mechan- 
ism in  this  whole  problem  of  absorption  and  secretion.  Changes 
of  both  a  quantitative  and  a  qualitative  character  must  of  course 
follow  the  changes  consequent  upon  any  variation  in  the  calibre 
of  the  blood  vessels  supplying  a  part.  With  blood  of  a  given 
composition,  it  is  evident  that  with  a  vaso-dilatation  more  blood 
will  flow  through  a  part,  and  so  the  opportunities  for  absorption 
or  secretion  whether  of  water  or  dissolved  substances  be  in- 
creased. But  such  quantitative  changes  in  the  blood  flow  through 
a  part  affect  at  the  same  time  the  chemical  and  physico-chemical 
character  of  the  cells  in  that  part,  and  so  a  series  of  qualitative 
changes  in  the  character  of  the  absorption  or  the  secretion  are 
added  to  the  quantitative  changes  already  noted.  It  is  these 
facts  that  we  have  to  bear  in  mind  when  we  attempt  the  analysis 
of  the  various  phenomena  that  characterize  absorption  and  se- 
cretion as  observed,  for  example,  in  a  mammal. 

The  organs  that  are  predominantly  secreting  organs  (kidney, 
salivary  glands,  stomach,  pancreas)  are  all  supplied  with  large 
arteries  and  when  these  glands  are  active,  their  arteries  are  di- 
lated. The  supply  of  highly  arterialized  blood  which  makes  pos- 
sible the  secretion  of  gastric  juice  (as  it  makes  possible  the  secre- 
tion of  urine)  makes  it  impossible  at  the  same  time  for  this  organ 
to  act  as  an  absorptive  organ.  And  experimentally  we  know  the 
stomach  to  act  indifferently  well  in  this  direction  as  far  as  water 
absorption  is  concerned.  Other  substances  can,  of  course,  be  ab- 
sorbed from  the  stomach  (alcohol,  salts)  and  be  secreted  into 
it  (various  salts)  independently  of  any  absorption  of  water. 
Failure  to  absorb  water  only  means,  of  course,  that  the  stomach 
wall,  and  the  (arterial)  blood  coursing  through  it  is  saturated 
with  water — the  three  phases  of  the  system  are  in  equilibrium 
so  far  as  their  water  content  is  concerned.  In  so  far  as  any  dis- 
solved substance  is  not  distributed  in  such  a  way  through  the  three 


246  DAN  BRIDGE  MEMORIAL 

systems  as  to  be  in  equilibrium,  it  must  move  into  the  stomach 
wall  and  the  blood  be  absorbed,  or  out  of  these  (be  secreted)  into 
the  gastric  contents  until  the  equilibrium  is  established.  When 
the  rich  supply  of  arterial  blood  to  a  secreting  organ  fails,  no 
secretion  occurs,  as  can  be  seen  particularly  well  in  the  kidneys, 
the  salivary  glands,  etc.,  when  their  blood  supply  is  cut  down 
either  through  experimental  constriction  of  the  arteries  supply- 
ing them,  or  when  the  vaso-constrictor  nerves  are  stimulated. 

It  is  true  that  no  secretion  may  occur  with  even  an  abundant 
arterial  flow  to  the  secreting  cells,  but  this  is  only  possible  if  the 
nonnal  chemistry  of  the  cells  constituting  the  secreting  mem- 
brane is  first  interfered  with,  as  after  poisoning  with  atropine, 
which  so  interferes  with  the  chemistry  of  oxidation  in  the  cells 
that  they  are  put  in  a  state  of  lack  of  oxygen  in  spite  of  all  that 
is  flowing  by  them. 

We  can  also  understand  the  meaning  of  some  of  the  morpho- 
logical changes  observed  in  the  cells  of  any  secreting  organ  so 
situated  as  to  have  alternate  periods  of  rest  and  activity.  While 
the  process  differs  somewhat  in  different  cells,  it  may  be  stated  in 
general  that  the  cells  become  larger  during  rest,  and  smaller 
during  activity.  The  interpretation  of  this  very  simple  fact  is  very 
complicated  as  given  by  different  authors.  Need  we  say  more 
than  that  they  absorb  water  (become  edematous)  when  arterial 
blood  is  scarce  and  they  cannot  get  rid  of  their  carbon  dioxide 
easily ;  and  that  they  secrete  water,  that  is,  shrink,  when  the  car- 
bonic and  other  acids  that  may  be  produced  in  the  cells  when 
oxygen  is  scarce,  are  removed  through  a  better  arterial  blood  sup- 
ply? With  the  swelling  of  the  cells  during  a  period  of  rest  there 
is  an  accumulation  of  granules  in  the  cells.  Most  extravagant 
interpretions  have  been  made  of  their  physiological  significance. 
Need  they  be  anything  more  than  protein  (including  mucin)  pre- 
cipitates occurring  in  the  bodies  of  the  cells  because  in  the  period 
of  glandular  rest  the  reaction  of  the  cell  protoplasm  tends  to  move 
toward  the  acid  side  ?  When  the  granules  disappear  during  glan- 
dular activity  it  simply  means  a  reversal  of  the  process — they 
go  back  into  solution  as  the  reaction  moves  back  toward  the  neu- 
tral point  or  the  alkaline  side.  The  changes  observed  during 
rest  and  activity  of  the  salivary  glands,  pancreas,  etc.,  therefore 


FISCHER  247 

become  similar  to  the  changes  of  "cloudy  swelHng""  observed  in 
the  liver  or  kidney  in  various  pathological  states  (including  inter- 
ferences with  the  arterial  blood  supply  to  the  cells  making  up 
these  organs). 

4.  After  what  has  been  said  it  is  evident  that  no  very  great 
differences  exist  between  the  essential  nature  of  absorption  and 
of  secretion.  Secretion  is  only  the  mirror  of  absorption.  This 
truth  seems  simple  enough,  and  yet  it  cannot  be  said  that  it  has 
received  any  special  attention  from  the  workers  in  experimental 
medicine  or  physiology.  And  yet  it  ought  to,  for  absorption  and 
secretion  in  a  complex  animal  bear  a  reciprocal  relation  to  each 
other.  It  is  because  this  fact  has  been  ignored  that  much  of  the 
present  confusion  exists  in  our  ideas  regarding  absorption  and 
secretion. 

An  adult  organism  in  order  to  continue  alive  has  to  maintain 
a  certain  constancy  of  physico-chemical  composition.  It  follows 
that  if  it  absorbs  anything  it  must  secrete  this  again  within  a 
reasonable  time  thereafter.  It  is  in  this  "reasonable  time"  and 
the  conditions  that  are  at  the  bottom  of  the  fact  that  this  "reason- 
able time"  has  to  intervene  between  the  absorption  and  the  secre- 
tion of  any  substance  that  makes  us  lose  the  connection  between 
the  two,  even  when  we  deal  with  the  absorption  and  secretion 
of  substances  (water,  certain  salts)  which  are  not  chemically 
changed  in  the  body.  When  these  facts  are  borne  in  mind,  the 
surprise  expressed  by  some  authors  that  atropine  or  morphine 
which  decrease  various  secretions  do  not  similarly  decrease  ab- 
sorption from  the  gut  or  the  peritoneal  cavity  disappears. 
Hardly!  These  substances  favor  the  formation  and  accumula- 
tion of  acids  in  the  tissues  of  the  body,  therefore,  no  secretion. 
Hence  we  should  discover  an  increased  absorption  of  water  after 
use  of  these  drugs,  which,  in  fact,  we  do.  Other  anesthetics  act 
like  morphine,  and  other  drugs  like  atropine-  When  we  use  such 
agents  in  our  experiments  we  have  to  remember  what  they  do, 
and  not  ignore  them  when  we  come  to  interpret  our  findings. 
Operations,  animal  boards  and  physiological  apparatus  produce 
collectively  effects  similar  to  drugs,  so  these  too  must  not  be 
ignored.  It  is  for  this  reason,  as  I  stated  above,  that  all  these 
procedures  must  be  reduced  to  a  minimum  if  we  would  complete 


248  DANDRIDGE  MEMORIAL 

our  analysis  of  just  what  constitutes  the  physiology  and  the  path- 
ology of  absorption  and  secretion. 

IV, 

After  these  remarks  on  the  general  nature  of  absorption  and 
secretion,  let  us  return  for  a  moment  to  the  explanations  of  these 
phenomena  that  have  been  given  by  other  authors,  and  select 
from  them  not  only  the  elements  which  we  ourselves  think  to  be 
correct,  but  point  out  at  the  same  time  with  the  help  of  a  few 
examples,  how  certain  experiments  which  have  long  stood  as  the 
bulwark  of  "physiological"  or  "vitalistic"  interpretations  of 
certain  life  phenomena  are  easily  explained  on  the  colloidal  basis, 
and  how  experiments  that  have  been  held  to  support  other  theo- 
ries of  absorption  fall  in  with  the  colloidal  one. 

1.  For  half  a  century  various  authors  have  held  that  filtra- 
tion plays  an  important  part  in  the  absorption  of  liquids.  Ac- 
cording to  definition,  filtration  represents  the  passage  of  a  liquid 
through  a  separating  membrane  of  some  sort  in  consequence  of 
differences  in  hydrostatic  pressure.  On  this  basis  it  has  been 
held  that  a  liquid  is  forced  from  the  lumen  of  the  gut  or  from 
the  peritoneal  cavity  into  the  blood  because  of  a  pressure  within 
the  gut  or  peritoneal  cavity  (produced  through  gas  or  the  action 
of  muscles  of  various  kinds)  which  exceeds  the  pressure  in  the 
blood.  Such  a  belief  has  been  supported  by  the  experiments  of 
Leubuscher  and  H.  J.  Hamburger,^^  who  found  that  with  an 
increase  of  intra-intestinal  or  intra-abdominal  pressure  there 
resulted  an  increase  in  absorption,  at  least  up  to  a  certain  point. 
Without,  for  a  moment  questioning  the  correctness  of  the  ex- 
perimental finding  itself  (a  serious  experimental  error  enters 
into  it)  we  know  that  such  an  intra-intestinal  or  intra-abdominal 
pressure  is  not  necessary  for  absorption.  E.  Waymouth  Reid-^ 
found  absorption  (of  water)  to  occur  from  the  intestine  of  the 
dog,  when  the  pressure  within  the  gut  was  decidedly  lower  than 
that  in  the  mesenteric  veins,  and  Hamburger  himself  describes 
experiments  in  which  he  observed  a  ready  absorption  of  water 
from  the  peritoneal  cavity  when  the  abdomen  of  the  animal  was 
opened  or  when  the  animal  was  dead.  After  what  has  been  said 
above   regarding   water  absorption  as   a   colloidal  phenomenon 


FISCHER  249 

these  findings  are  entirely  to  be  expected.  What  is  needed  is  an 
interpretation  of  Leubuscher  and  Hamburger's  experiments  with 
changes  in  pressure.  Leubuscher's  result  has  been  explained  by 
saying  that  through  increased  intra-intestinal  pressure  the  folds 
of  the  intestinal  mucosa  are  smoothed  out,  and  so  an  increased 
surface  of  the  gut  is  rendered  available  for  absorption.  But  this 
explanation  has  not  been  accepted  as  complete  by  Hamburger, 
who  found  an  increased  absorption  from  the  gut  with  every 
increase  in  pressure  up  to  a  certain  point,  even  after  surrounding 
the  intestine  with  a  wire  cage  which  prevented  its  unfolding. 
In  explanation  of  Hamburger's  result,  I  would  agree  with  the 
view  that  with  the  first  increase  in  pressure  the  flow  of  blood 
out  of  the  veins  is  favored.  In  consequence  of  this  the  blood 
flow  through  the  gut  is  favored  ana  so  the  conditions  for  ab- 
sorption- With  a  further  increase  in  pressure,  the  blood  vessels 
are  compressed,  and  now  the  blood  flow  is  diminished,  in  conse- 
quence of  which  a  decrease  in  absorption  is  observed,  as  Ham- 
burger found. 

I  am  not  even  inclined  to  accept  the  view  of  those  authors, 
who,  while  unwilling  to  look  upon  filtration  as  an  important 
factor  or  as  the  most  important  factor  in  the  passage  of  liquid 
from  one  region  to  another,  nevertheless  consider  that  it  is  of 
some  physiological  importance.  To  my  mind,  this  cannot  have 
a  magnitude  any  greater  than,  say,  the  theoretical  "solubility"  of 
quartz  in  water,  for  the  membranes  in  health  through  which 
water  is  supposed  to  be  forced  are  built  up  of  emulsion  colloids, 
and  the  differences  in  pressure  available  in  the  body  for  filtra- 
tion through  the  membranes  existing  here,  have  a  value  approxi- 
mating zero,  when  compared  with  the  enormous  pressures  re- 
quired in  the  laboratory  to  force  water  through  the  thinnest 
layers  of  such  emulsion  colloids  as  gelatine. 

2,  The  question  of  osmotic  pressure  (even  as  modified 
through  the  conception  that  the  surface  layer  of  the  cells  is 
lipoidal  in  character)  in  the  problem  of  water  absorption  from 
the  gut  needs  no  special  discussion — its  inadequacy  to  explain 
the  phenomena  of  absorption  as  observed  here  is  admitted  on 
all  sides.  That  it  continues  to  be  widely  held  as  of  fundamental 
biological  importance  results  no  doubt   from  the   fact  that  we 


250  DAN  BRIDGE  MEMORIAL 

have  had  nothing  more  adequate  to  substitute  for  it ;  and  any 
number  of  biological  workers  have  been  unwilling  to  believe  that 
a  present  inability  to  explain  on  a  purely  physico-chemical  basis 
all  the  phenomena  observed  in  the  processes  of  absorption  or 
secretion  presages  that  such  an  explanation  will  never  be  forth- 
coming, and  that,  in  consequence,  support  is  lent  "physiological" 
or  "vitalistic"  conceptions  of  absorption  or  secretion.  It  seems 
to  me  that  on  the  basis  of  what  has  been  said  in  these  pages  and 
in  some  of  my  previous  papers,  we  are  now  in  a  position  where 
we  not  only  may,  but  must,  discard  the  osmotic  conception  of 
cell  behavior  so  far  as  water  absorption  is  concerned.  We  must 
also  discard  it  so  far  as  the  absorption  of  dissolved  substances  is 
concerned. 

If  cells  were  surrounded  by  semi-permeable  films,  as  is  de- 
manded by  the  osmotic  theory  of  water  absorption,  dissolved 
substances  would  neither  get  into  them  nor  out  of  them.  Yet 
both  these  processes  must  be  possible,  as  well  as  the  movement 
of  water  into  and  out  of  cells,  otherwise  their  life  would  cease. 
Dissolved  substances  get  into  and  out  of  cells  by  diffusion.  The 
role  of  this  factor  has  been  recognized  and  discussed  as  active 
in  the  processes  of  absorption  and  secretion  since  the  days  of 
Carl  Ludwig.  R.  Heidenhain  succeeded  in  minimizing  the  value 
of  this  process  in  the  analysis  of  the  whole  problem  by  showing 
that  an  absorbed  fluid  or  a  secretion  usually  differs  in  quanti- 
tative composition  from  the  source  from  which  it  was  derived. 
On  this  is  based  his  belief  in  the  selective  "physiological"  char- 
acter of  absorption  and  secretion.  There  is  nothing  surprising 
about  these  phenomena  to  us.  We  expect  them,  in  fact.  As  has 
been  said,  a  solution  is  never  absorbed  {or  secreted)  as  such. 
Whenever  a  solution  is  seen  to  be  absorbed  (or  secreted),  we  are 
observing  the  composite  of  the  absorption  (or  the  secretion)  of 
the  solvent  plus  the  absorption  (or  secretion)  of  each  individual 
substance  dissolved  in  that  solvent-  When  any  solution  is  intro- 
duced into  the  intestine,  for  example,  each  one  of  the  dissolved 
substances  diffuses  into  the  wall  of  the  intestine  until  an  equi- 
librium is  established  in  the  distribution  of  each  of  these  sub- 
stances between  the  (liquid)  phase  represented  by  the  solution 
and  the  more  solid  phase  represented  by  the   (colloidal)   intes- 


FISCHER  251 

tinal  wall.  Similarly,  every  substance  present  in  the  intestinal 
wall  tends  to  diffuse  out  into  the  solution  to  the  establishment 
of  an  equilibrium. 

In  biological  material  it  has  been  very  generally  assumed  that 
the  distribution  of  dissolved  substances  between  two  such  phases 
attains  an  equilibrium  when  the  concentration  of  any  dissolved 
substance  is  the  same  in  both.  Such  an  a  priori  conclusion  is 
entirely  unjustified.  We  deal  in  this  problem  with  the  distribu- 
tion of  a  dissolved  substance  between  water  and  a  colloid,  and, 
as  we  know  from  the  facts  now  available  on  this  subject,  equi- 
librium may  be  reached  when  the  dissolved  substance  is  con- 
tained in  less,  the  same,  or  a  higher  concentration  in  the  colloid 
than  in  the  solution  surrounding  it.  Now,  while  the  absorptive 
membrane  is  trying  to  get  into  equilibrium  with  the  solution  to 
be  absorbed  on  the  one  side,  it  is  also  trying  to  get  into  equi- 
librium with  the  blood  on  the'  other.  The  whole  absorptive 
system  therefore  really  consists  of  three  phases,  (1)  the  material 
to  be  absorbed,  (2)  the  colloidal  absorbing  membrane,  (3)  the 
liquid  colloidal  blood.  The  problem  of  the  "selective"  absorp- 
tion of  the  dissolved  substance  is  the  problem  of  the  agencies 
concerned  in  establishing  an?  equilibrium  between  all  the  various 
dissolved  substances  in  these  three  phases. 

As  is  familiar  to  everyone,  the  factors  of  greatest  importance 
in  such  a  problem  are  the  character  of  the  various  colloids  con- 
cerned, and  their  physico-chemical  state  as  determined  through 
the  presence  of  acids,  alkalies,  salts  and  various  non-electrolytes ; 
the  nature  of  the  dissolved  substance  to  be  absorbed,  as  its  rate 
of  diffusion ;  the  presence  or  absence  of  lipoids  in  the  colloidal 
absorbing  membrane  and  in  the  blood,  etc.  In  other  words,  the 
laws  of  adsorption,  of  partition,  and  of  chemical  combination  are 
all  at  work.  To  the  process  of  simple  diffusion  in  this  matter  of 
absorption  (or  secretion)  become  added  therefore  a  series  of 
secondary  phenomena  that  obscure  its  purity. 

To  illustrate  what  has  been  said,  let  us  try  to  follow  the  rela- 
tively simple  process  of  the  absorption  of  a  strong  (so-cal'ed 
hypertonic)  sodium  chloride  solution  when  this  is  introduced  into 
the  peritoneal  cavity,  or  into  the  intestine.  Both  the  water  and 
the  salt  begin  immediately  to  diffuse  into  the  absorbing  mem- 


252  DANDRIDGE  MEMORIAL 

brane.  As  this  progresses,  the  concentration  of  the  sodium 
chloride  in  the  absorbing  membrane  rises.  This  rise  in  concen- 
tration so  affects  the  colloids  of  the  absorbing  membrane  ihat 
they  stop  taking  up  water,  or,  if  sufficiently  strong,  an  actual 
secretion  of  water  into  the  peritoneum  or  the  gut  may  follow. 
While  this  is  occurring,  an  equilibrium  is  tending  to  be  estab- 
lished between  the  concentration  of  the  sodium  chloride  in  the 
solution  undergoing  absorption  and  the  sodium  chloride  in  the 
absorbing  membrane.  But  this  is  never  attained  under  normal 
circumstances,  because  the  salt  in  the  absorbing  membrane  is  at 
the  same  time  trying  to  get  into  equilibrium  with  the  sodium 
chloride  in  the  blood.  Now,  since  this  is  circulating,  it  is  evident 
that  the  equilibrium  is  constantly  being  broken  down  toward  the 
side  of  the  blood-  In  consequence  of  this,  more  and  more  salt 
must  move  over  into  the  blood  (be  absorbed).  But,  as  this 
occurs,  the  state  of  the  colloids  of  the  absorbing  membrane  again 
returns  to  a  more  "normal"  state  and  so  the  absorption  of  water, 
which  could  not  occur  before,  can  again  take  place. 

With  a  dilute  (a  hypotonic)  solution  of  sodium  chloride  the 
water  does  not  meet  with  so  great  a  resistance  to  absorption,  and 
it  is  possible  for  a  dilute  salt  solution  to  become  more  and  more 
concentrated  as  the  water  is  (the  more  rapidly  of  the  two)  ab- 
sorbed from  it. 

Even  salt  solutions  isotonic  with  the  blood  must  be  absorbed. 
Though  such  a  solution  cannot  be  absorbed  on  the  osmotic  basis 
because  no  osmotic  differences  exist  in  such  a  case  to  make  the 
water  move,  there  is  no  difficulty  in  interpreting  what  happens 
on  the  colloidal  basis.  Let  the  colloids  of  the  absorbing  mem- 
brane take  a  little  water  from  the  isotonic  solution  and  salt  must 
quickly  follow,  for  now  its  concentration  is  no  longer  in  equi- 
librium with  that  of  the  sodium  chloride  in  the  absorbing  col- 
loidal membrane.  Then  more  water  goes  in,  and  then  more  salt, 
until  all  is  absorbed.  Or  we  could  start  the  absorption  by  having 
a  little  salt  go  in  first  and  then  the  water,  etc.,  for  if  the  truth  be 
told  we  do  not  yet  know  just  what  concentration  characterizes 
the  "isotonic"  solution,  nor  shall  we  until  the  colloidal  consti- 
tution of  living  matter  has  been  adequately  taken  into  account. 

In  a  final  word,  let  it  be  added  that,  on  the  basis  of  these 


FISCHER  253 

conceptions  of  absorption,  we  experience  no  difficulty  in  under- 
standing why  any  solution  remaining  for  longer  periods  in  the 
peritoneal  cavity  or  in  the  intestine  may,  while  it  is  being  "ab- 
sorbed," has  substances  found  in  the  blood  or  tissues  appear  in 
it  which  it  did  not  originally  contain.  As  dissolved  substances 
diffuse  out  of  a  solution  undergoing  absorption  into  the  absorb- 
ing membrane  until  an  equilibrium  is  established,  just  so,  of 
course,  must  the  substances  contained  in  the  absorbing  mem- 
brane tend  to  diffuse  into  the  solution.  It  has  been  generally 
held  that  this  diffusion  of  salts  (and  other  substances)  out  of  an 
absorbing  membrane  into  a  solution  that  is  being  absorbed  con- 
stitutes "an  attempt  to  establish  osmotic  equilibrium  between  the 
two."  As  a  matter  of  fact  such  a  conclusion  is  premature  if 
nothing  more.  We  do  not  yet  know  all  the  factors  involved  in 
determining  the  point  of  equilibrium  in  the  body  in  the  distri- 
bution of  the  various  dissolved  substances  between  the  phases 
concerned.  One  thing,  however,  is  certain  and  that  is  that  the 
final  equilibrium  is  not  a  simple  osmotic  equilibrium.  This  is 
clearly  enough  evidenced  not  alone  by  the  well-known  fact  that 
the  physiological  behavior  of  different  salts,  in  this  process  of 
absorption,  for  example,  bears  no  relation  to  the  osmotic  con- 
centration of  the  dissolved  substances,  but  by  the  further  fact 
that  the  distribution  of  most  substances  between  a  colloid  and  a 
solution  is  practically  never  the  same  in  both.  The  "selective" 
character  of  absorption"  and  secretion  depends  upon  the  fact  that 
the  absorption  and  secretion  of  water  in  the  living  organism  is  a 
process  entirely  separate  from  the  absorption  and  the  secretion 
of  dissolved  substances,  and  of  the  latter  each  moves  at  its  own 
rate,  and  is  influenced  in  its  mvvem£nt  by  factors  that  may  not 
affect  the  others  in  the  same  way  or  to  the  same  degree.  When 
these  facts  are  remembered  the  "selective"  character  of  both 
absorption  and  secretion  cease  to  produce  astonishment — it 
would  be  more  marvelous  were  it  not  selective. 

3-  The  workers  in  physiology  and  experimental  medicine, 
who  have  called  attention  to  the  "secretory"  and  "physiological" 
activities  of  absorbing  and  secreting  membranes  and  to  the 
"physiologische  Triebkraft"  situated  in  them,  are  deserving  of 
blame  or  praise  depending  upon  whether  they  have  used  these 


254  DANDRIDGE   MEMORIAL 

words  in  the  despairing  attitude  of  those  biological  workers  who 
believe  that  life  phenomena  will  never  be  interpretable  solely  in 
the  terms  of  the  physical  sciences,  or  as  convenient  heads  under 
which  to  group  certain  of  the  phenomena  of  absorption  and  se- 
cretion which  could  not  be  so  analyzed  at  the  time  that  they  pros- 
ecuted their  scientific  studies.  But  the  necessity  of  retaining 
these  terms,  even  in  the  latter  sense,  may  now  largely  disappear. 
The  "secretory"  activities  of  absorbing  and  secreting  membranes 
as  evidenced  through  their  "selective"  absorption  and  secretion 
of  water  and  dissolved  substances  we  have  already  discussed  in 
the  preceding  paragraphs.  The  "physiological"  activity  of  such 
membranes  retains  a  meaning  only  in  the  sense  that  the  absorb- 
ing and  secreting  membranes  of  multicellular  organisms  contain 
living  cells  and  in  each  of  these  there  are  occurring  well  ordered 
series  of  chemical  and  physico-chemical  reactions  which  are 
capable  of  influencing  the  colloidal  constitution  of  these  mem- 
branes. To  do  this  is  to  influence  the  nature  of  the  phases  and 
the  conditions  of  equilibrium  in  our  secretory  systems,  in  other 
words,  secretion  and  absorption.  But  these  reactions  are  not 
impossible  to  analyze. 

The  need  for  the  "physiologische  Triebkraft"  also  disappears. 
Such  was  originally  called  upon  for  help  in  the  contemplation  of 
such  a  fact  as  that  the  absorption  of  a  solution  can  occur  from 
the  intestine,  for  example,  when  the  pressure  under  which  it 
stands  in  the  lumen  of  the  gut  is  less  that  the  pressure  of  the 
blood  in  the  mesenteric  veins  through  which  it  is  being  absorbed 
(E.  Waymouth  Reid).  Such  a  view  regards  absorption  as  a 
process  in  which  water  is  forced  into  the  tissues.  This  is  not 
what  happens.  It  is  sucked  in,  and  such  a  process  can  occur 
even  when  the  hydrostatic  pressure  in  the  veins  happens  to  be  a 
few  millimetres  above  that  in  the  lumen  of  the  intestine.  The 
pressures  produced  in  the  swelling  of  emulsion  colloids  are 
enormous  as  compared  with  the  highest  hydrostatic  (arterial 
blood)  pressures  ever  observed  in  animals  possessed  of  a  circu- 
lation. The  use  of  "physiological"  poisons  to  illuminate  the 
"physiological"  element  in  absorption  or  secretion  proves  noth- 
ing. Such  poisons  simply  constitute  a  direct  or  indirect  means 
of  altering  the  physico-chemical  state  of  the  absorbing  or  se- 


FISCHER  255 

•creting  structures.  And  is  it  not  the  problem  of  physiology  to 
state  in  terms  of  physics  and  chemistry  just  what  this  "normal" 
absorption  and  secretion  is? 

When  we  use  a  "physiological"  poison  we  have  to  explain  the 
action  of  the  poison  along  with  what  constitutes  "normal"  ab- 
sorption and  secretion. 

Nothing  has  perhaps  so  effectively  hampered  the  acceptance 
of  the  belief  that  absorption  and  secretion  would  ultimately 
prove  themselves  completely  analysable  physico-chemically,  and 
fostered  the  continuation  of  the  "physiological,"  "secretory," 
etc.,  notions  of  absorption  and  secretion  as  a  series  of  experi- 
ments first  described  by  R-  Heidenhain,  and  more  recently  re- 
peated in  modified  form  by  E.  Waymouth  Reid  and  Otto  Cohn- 
heim.  The  most  striking  of  these  is  the  often  quoted  experi- 
mental finding  that  a  dog  will  absorb  his  own  blood  serum.  A 
word  regarding  the  experiments  of  this  character  serve  to  show 
how  they  are  interpretable  on  the  basis  of  the  colloidal  theory  of 
water  secretion  and  absorption.  In  not  one  of  these  experiments, 
except  zvhere  the  possibility  of  the  presence  of  proteolytic  fer- 
ments is  not  excluded,  is  the  serum  or  plasma  completely  ab- 
sorbed. The  reason  why  some  is  absorbed,  but  never  all,  is  clear 
from  the  following: 

Blood  serum  and  blood  plasma  are  not  blood ;  they  are  blood 
minus  much  of  its  emulsion  colloid  content.  They  are  not  solu- 
tions in  which  all  the  water  they  contain  is  bound  to  colloidal 
material  as  in  normal  blood,  but  they  contain  "free"  water  over 
and  above  that  necessary  to  saturate  the  colloids  remaining  in 
the  "serum"  or  the  "plasma."  When  they  are  introduced  into 
the  intestine  they  are  therefore  absorbable  but  only  in  so  far  as 
they  contain  free  water  (and  a  certain  proportion  of  salts,  urea, 
etc.)  The  absorption  comes  to  a  halt  as  soon  as  water  has  been 
absorbed  down  to  the  point  where  water  is  combined  with  colloid. 
In  these  experiments,  things  are  therefore  not  the  same  on  both 
sides  of  the  absorbing  membrane.  The  animal  does  not  absorb 
serum  or  plasma  as  such,  much  less  what  these  authors  seem  at 
times  to  try  to  have  us  believe,  namely,  something  identical  with 
blood  itself.  The  animal  absorbs  some  water  and  a  few  dis- 
solved substances,  and  it  does  this  for  the  same  simple  reasons 


256  DANDRIDGE  MEMORIAL 

that  it  absorbs  under  similar  circumstances  an  ordinary  "physio- 
logical" salt  solution. 

4.  Of  the  different  factors  that  are  catalogued  in  our  treatises 
on  physiology,  and  which  have  at  various  times  and  in  various 
ways  been  looked  upon  as  active  in  this  problem  of  absorption 
and  secretion,  only  one  remains  to  be  discussed — that  of  imbibi- 
tion. What  Adolph  Fick^°  has  called  molecular  imbibition  is  but 
another  term  for  what  we  to-day  call  the  absorption  of  water 
by  an  emulsion  colloid.  It  is,  therefore,  of  interest  that  mention 
is  made  of  imbibition  as  being  important  in  the  general  problem 
of  absorption  as  far  back  as  1881.^^  But  the  real  significance  of 
imbibition  as  a  factor  concerned  in  absorption  was  only  pointed 
out  more  recently  by  H.  J.  Hamburger-^-  This  author  correctly 
emphasized  the  theoretical  importance  of  his  observation  that 
anim.als  absorb  various  solutions  from  their  peritoneal  (and  other 
serous)  cavities  after  death.  While  we  cannot  agree  with  the 
details  of  his  ideas  outlining  the  way  in  which  the  forces  of 
imbibition  act  normally,  a  discussion  into  which  it  is  not  necessary 
to  go  here,  there  is  no  disputing  his  claims  that  imbibition  plays 
a  role.  But  Hamburger  does  not  regard  imbition  as  the  most 
significant  factor  in  absorption,  and  continues  to  hold  to  the  ideas 
of  filtration,  osmotic  pressure  and  the  "mitschleppende  Wirkung" 
of  the  circulation  as  also  concerned  in  the  process.  Nor  does 
this  author  suggest  any  way  by  which  a  fluid  absorbed  by  imbibi- 
tion is  again  gotten  rid  of.  In  view  of  all  this  it  seems  to  me  that 
we  owe  a  special  debt  to  Franz  Hofmeister,^^  who,  as  early  as 
1891,  pointed  out  that  the  salts  which  make  (partially)  water 
soaked  gelatine  discs  give  off  their  water  (secrete  it)  are 
identical  with  the  so-called  saline  cathartics,  and  suggested  that 
the  two  processes  are  in  essence  the  same.  In  spite  of  the  nu- 
merous papers  on  alimentary  absorption  and  secretion,  and  on 
the  mode  of  action  of  the  saline  cathartics  that  have  appeared 
since  Hofmeister's  writings,  there  seems  little  question  that  we 
are  destined  to  return  to  Hofmeister's  conclusions,  and  find  in 
them  not  only  an  explanation  of  the  mode  of  action  of  these 
cathartic  salts,  but  a  model  of  that  which  constitutes  the  essence 
of  absorption  and  secretion. 

5.  The  analysis  of  the  problems  of  absorption  and  secretion 


FISCHER  257 

could  already  be  carried  with  entire  safety  beyond  the  limits 
outlined  in  this  and  previous  papers  which  have  had  as  their 
chief  aim  the  mere  establishment  of  the  thesis  that  the  colloids 
and  their  physical  state  determine  both  the  quantitative  and  the 
qualitative  character  of  the  absorption  and  the  secretion  of  water 
and  dissolved  substances  by  protoplasm.^*  This  will  be  the  pur- 
pose of  a  future  communication.  In  passing,  however,  attention 
must  be  called  to  the  excellent  service  that  will  be  rendered  the 
further  analysis  of  the  problem  by  the  theories  of  the  colloidal 
state  which  are  becoming  progressively  more  clearly  defined. 
Especially  helpful  to  the  biological  worker  must  become  the  con- 
clusions of  Wolfgang  Pauli,^^  and  his  co-workers,^^  more  par- 
ticularly Hans  Handovsky,^^  and  Karl  Schorr.^*  With  them  we 
could,  for  example,  define  every  increase  in  the  absorption  of 
water  by  a  tissue  as  an  increase  in  the  degree  of  the  hydration 
of  the  colloids  contained  in  it,  while  secreticii  itself  and  the 
various  processes  that  favor  secretion  represen,  in  toto  means 
which  decrease  such  a  hydration. 

The  theoretical  elucidations  of  the  process  of  absorption  and 
secretion  of  dissolved  substances  will  necessitate  that  adequate 
use  be  made  of  Wolfgang  Ostwald's^^  work.  Ostwald  has 
shown  that  the  mathematical  formulas  of  adsorption  are  appli- 
cable to  the  process  of  absorption  (intoxication)  as  shown  in 
certain  fresh  water  animals  (Ganimartis)  when  they  are  placed 
in  solutions  of  various  kinds.  It  is  evident  that  these  animals 
swimming  about  in  a  solution  are  no  differently  situated  than  a 
group  of  cells,  say  in  the  mucous  membrane  of  the  intestine 
which  are  bathed  by  such  a  solution.  But  Ostwald  has  developed 
the  biological  significance  of  what  represents  in  a  sense  the 
mirror  image  of  the  absorption  formula,  namely,  the  washing- 
out  formula.  This  may  be  used  to  express  mathematically  the 
"toxic  effect"  of  distilled  water  upon  these  animals — an  effect 
brought  about  by  the  diffusion  of  the  salts  contained  in  the  animal 
out  into  the  distilled  water-  It  is  evident  that  the  leaching  out 
of  dissolved  substances  from  the  kidney  by  the  pure  water 
originally  secreted  from  the  organ  constitutes  the  parallel  of  this 
"toxic  effect"  of  the  distilled  water  on  Gammanis.  Ostwald  has 
further  shown  that  the  effect  of  a  solution  having  but  one  salt 


258  DANDRIDGE  MEMORIAL 

dissolved  in  it  is  the  composite  of  the  absorption  effect  of  that 
salt  plus  the  washing-out  effect  of  all  the  other  salts  contained 
in  the  animal  but  absent  from  the  solution  that  is  being  experi- 
mentally employed.  This  phenomenon  has  its  analogue  in  the 
experimental  absorption  of  any  pure  solution  from  the  intestinal 
tract  of  a  mammal,  for  example,  in  which,  as  was  noted  above, 
there  is  a  "secretion"  of  dissolved  substances  from  the  intestinal 
wall  into  the  gut,  while  the  dissolved  substance  originally  intro- 
duced is  being  "absorbed," 

SUMMARY. 

In  this  paper  is  continued  the  discussion  of  absorption  and 
secretion  in  the  higher  animals  from  the  viewpoint  of  colloid 
chemistry.  Absorption  and  secretion  are  defined  as  mirror 
images  of  each  other,  not  alone  because  the  one  process  is  the 
biological  reverse  of  the  other,  but  because  the  conditions  that 
favor  the  one,  liinder  the  other,  and  vice  versa.  After  reviewing 
the  evidence  which  shows  that  no  essential  difference  exists  be- 
tween absorption  and  secretion  in  a  unicellular  organism  and 
absorption  and  secretion  in  a  multicellular  organism,  it  is  pointed 
out  that  all  which  remains  to  characterize  absorption  and  secre- 
tion in  the  multicellular  organism  is  its  one-sided  character — that 
the  intestine  is,  for  example  (predominantly),  an  absorbing 
organ,  while  the  kidney  is  (predominantly)  a  secreting  one. 
This  difference  between  the  behavior  of  any  unicellular  organism 
and  the  individual  absorbing  or  secreting  cell  of  a  multicellular 
organism  is  brought  into  connection  with  the  fact  that  while  the 
former  is  surrounded  on  all  sides  by  the  same  medium,  the  latter 
is  in  contact  with  different  media  at  different  parts  of  its  proto- 
plasm. Absorption  and  secretion  in  the  former  represent  the 
single  attempt  of  getting  into  equilibrium  with  the  one  medium 
surrounding  it ;  in  the  latter,  the  attempt  to  get  into  equilibrium 
with  two  or  more  media.  Out  of  the  latter  grows  the  fact  that 
absorption  and  secretion  in  the  higher  animals  occur  predomi- 
nantly in  one  direction. 

The  fact  is  emphasized  that  the  absorption  or  the  secretion  of 
any  solution  is  never  a  single  process — it  is  the  composite  of  the 
absorption  or  the  secretion  of  the  solvent  plus  the  absorption  or 


FISCHER  259 

the  secretion  of  each  individual  substance  dissolved  in  that 
solvent.  A  series  of  experiments  on  peritoneal  absorption 
is  then  detailed.  It  is  pointed  out  that  the  absorption  of  the 
solvent,  the  water,  from  the  injected  solutions  is  identical  with 
the  absorption  of  water  by  such  emulsion  colloids  as  fibrin  or 
gelatine  when  these  are  exposed  to  the  same  external  conditions. 
Peritoneal  absorption  is  next  shown  to  parallel  point  for  point 
absorption  from  the  intestinal  tract,  and  both  of  these  are 
then  shown  to  be  the  mirror  image  of  secretion  as  occurring  from 
the  kidney.  Evidence  is  adduced  to  show  that  the  formation  of 
lymph  is  analagous  to  the  secretion  of  urine.  The  absorption  and 
secretion  of  dissolved  substances,  and  their  selective  character, 
are  held  to  be  dependent  upon  the  unequal  distribution  of  the 
dissolved  substances  between,  what  we  may  call  broadly  speak- 
ing, three  phases  (water,  secreting  or  absorbing  tissues,  blood) 
that  constitute  every  absorptive  or  secretory  system  in  one  of  the 
higher  animals ;  and  it  is  pointed  out  how  this  is  entirely  analagous 
and  explainable  on  the  same  grounds  as  are  inequalities  observed 
in  the  distribution  of  dissolved  substances  between  three  such 
phases  as  water,  a  solid  colloid  and  a  liquid  colloid. 

The  prevailing  theories  of  absorption  and  secretion  are  touched 
upon  in  brief  review  and  criticized.  Filtration  is  held  to  be  of 
no  real  interest  in  the  problem  under  physiological  conditions. 
Diffusion  is  looked  upon  as  of  fundamental  importance  both  in 
the  matter  of  determining  the  rate  of  absorption  and  secretion 
and  their  character,  though  owing  to  the  colloid  constitution  of 
living  matter  diffusion  does  not  appear  in  as  pure  a  form  in  bio- 
logical material  as  in  a  homogeneous  solvent.  The  osmotic  con- 
ception of  water  absorption  is  cast  aside.  It  is  briefly  indicated 
how  experiments  which  are  designed  to  support  "physiological," 
"secretory"  or  "vitalistic"  conceptions  of  absorption  or  secretion 
do  not  do  so,  but  are  interpretable  in  the  terms  of  the  colloidal 
theory  of  water  absorption  and  the  inequalities  in  the  distribution 
of  dissolved  substances  between  the  various  phases  constituting 
the  absorptive  or  secretory  system.  As  of  greatest  value  in  the 
theoretical  formulation  of  the  problem  are  held  certain  scattered 
remarks  to  the  effect  that  imbibition  plays  a  role  in  the  process 
of  absorption  (von  Wittich)  and  the  clearer  experimental  demon- 


260  DAN  BRIDGE  MEMORIAL 

stration  of  this  fact  by  Hamburger;  and  in  the  problem  of  secre- 
tion Hofmeister's  clear-cut  expression  of  the  truth  that  secretion 
of  fluid  into  the  intestine  under  the  influence  of  the  saline  ca- 
thartics is  identical  with  the  loss  of  water  by  swollen  gelatine 
plates  when  immersed  in  solutions  of  these  same  salts. 

BIBLIOGRAPHY. 

1  Martin  H.  Fischer:  American  Journal  of  Physiology,  20,  330  (1907)  ; 
Pfliiger's  Arch.,  124,  69  (1908)  ;  Journal  of  the  American  Medical  Asso- 
ciation, 51,  830  (1908);  Pfliiger's  Arch.,  125,  99  (1908);  Ibid.,  125,  396 
(1908);  Ibid.,  127,  1  (1909);  Kolloidchemische  Beihefte,  1,  93  (1910);  a 
running  account  is  found  in  "Edema,"  New  York,  1910. 

2  Martin  H.  Fischer:  "Edema,"  184,  New  York,  1910. 

3  R.  Heidenhain :  Hermann's  Handbuch  der  Physiologic,  5,  Leipzig, 
1883;  Pfliiger's  Arch.,  56,  579  (1894). 

4  E.  Waymouth  Reid :  Schafer's  Text-Book  of  Physiology.  1,  261, 
London  and  Edinburgh,  1898;  Phil.  Trans.  Royal  Soc,  192,  231  (1900); 
Journal  Physiol.,  26,  436  (1901). 

5  E.  H.  Starling:  Schafer's  Text-Book  of  Physiology,  1,  285,  London 
and  Edinburgh,  1898.  Oppenheimer's  Handbuch  der  Biochemie,  3,  206. 
Jena,  1909. 

6  H.  J.  Hamburger :  Osmotischer  Druck  und  lonenlehre,  2,  95,  Wies- 
baden, 1904. 

7  E.  Overton :  Nagel's  Handbuch  der  Physiologic,  2,  774,  Braun- 
schweig, 1907. 

8  O.  Cohnheim :  Nagel's  Handbuch  der  Physiologic,  2,  607,  Braun- 
schweig, 1907. 

9  R.  Hober :  Koranyi-Richter,  Physikalische  Chemie  und  Medizin,  1, 
295,  Leipzig,  1907. 

10  Starling  and  Tubby:  Journal  of  Physiol.,  14,  140  (1894);  Starling: 
Schafer's  Text-Book  of  Physiology,  1,  304.  Edinburgh  and  London,  1898. 

11  Orlow:  Pfluger's  Archiv,  59,  170  (1895). 

12  H.  J.  Hamburger:  Arch.  f.  Anat.  u.  Physiol.,  281   (1895). 

13  C.  Schmidt :  Vierordt's  Daten  und  Tabellen,  97,  Jena,  1888. 

14  J.  Munk  and  Rosenstein :  Arch.  f.  Physiol.,  376,  1890. 

15  Martin  H.  Fischer:  Edema,  180,  New  York,  1910.  See  chapter  on 
urinary  secretion. 

16  James  J.  Hogan  and  Martin  H.  Fischer :  Kolloidchemische  Beihefte, 
3  (1912). 

17  Voit  and  Bauer:  Zeitschr.  f.  Biol.,  5,  536  (1869). 

18  R.  Heidenhain:  Pfliiger's  Arch.,  56,  379  (1894),  62,  331   (1896). 

19  Franz  Hofmeister:  Arch.  f.  exp.  Path.  u.  Pharm.,  28,  210  (1891). 

20  H.  J.  Hamburger :  Osmotischer  Druck  und  lonenlehre,  2,  168,  Wies- 
baden, 1904,  where  reference  to  his  earlier  papers  will  be  found. 

21  Rudolph  Hober :  Pfluger's  Arch.,  from  70  on ;  see  his  many  papers 
during  the  years  1898  to  date. 

22  G.  B.  Wallace  and  A.  R.  Cushnv:  Am.  Journal  Physiol.,  1,  411 
(1898)  :  Pfluger's  Arch.,  77,  202  (1899). 

23  Otto  Cohnheim:  Zeitschr.  f.  Biol.,  21,  85  (1897);  22,  56  (1898); 
26,  427  (1901). 

24  E.  Waymouth  Reid:  Journd  of  Physiol.,  21,  85  (1897);  22,  56 
(1898);  26,  427  (1901). 

25  G.  Kovesi:  Centralbl.  f.  Physiol.,  11,  553  (1897). 

26  Martin  H.  Fischer :  Edema,  184,  New  York,  1910. 


FISCHER  261 

27  For  a  discussion  of  the  nature  and  the  cause  of  cloudy  swelling  see 
Martin  H.  Fischer:  Kolloid  Zeitsch.,  8,  159  (1911);  8,  201  (1911);  or 
Nephritis,  New  York,  1911. 

28  H.  J.  Hamburger:  Osmotischer  Druck  und  lonenlehre,  2,  176,  Wies- 
baden, 1904. 

29  E.  W.  Reid:  Philosoph.  Trans.  Royal  Soc,  192,  231   (1900). 

30  Adolph  Fick :  Medizinische  Physik.,  3te  Aufl.,  31,  Braunschweig, 
1885. 

31  W.  von  Wittich :  Hermann's  Handbuch  d.  Physiol.,  5,  2ter  Theil, 
Leipzig,  1881. 

32  H.  J.  Hamburger :  Osmotischer  Druck  und  lonenlehre,  2,  108  and 
164,  Wiesbaden,  1904. 

33  Franz  Hofmeister:  Arch.  f.  exp.  Path,  und  Pharm.,  28,  210  (1891). 

34  For  a  discussion  of  the  role  of  lipoids  in  absorption,  which  I  hold 
do  not  act  as  lipoidal  films  about  cells,  see  my  Edema,  85  and  160,  New 
York,  1910. 

35  Wolfgang  Pauli :  Kolloid  Zeitschr.,  7,  214  (1910). 

36  Wolfgang  Pauli  und  Hans  Handovsky:  Biochem.  Zeitschr.,  18,  340 
(1909). 

Z7  Hans  Handovsky:  Kolloid  Zeitschr.,  7,  183  and  267  (1910),  where 
references  to  earlier  papers  will  be  found. 

38  Karl  Schorr:  (Cited  by  Pauli  and  Handovsky). 

39  Wolfgang  Ostwald:  Pfliiger's  Arch.,  120,  19  (1907);  Kolloid  Zeit- 
schr., 2,  108  and  138  (1907);  Uo.  Ostwald  und  A.  Dernoscheck:  Kolloid 
Zeitschr.,  6,  297  (1910). 


THE   RELATION   BETWEEN   THE   CYTO-RETICULUM 

AND  THE  FIBRIL  BUNDLES  IN  THE  HEART 

MUSCLE  CELL  OF  THE  CHICK.* 


HENRY  LEWIS  WIEMAN. 


In  the  great  mass  of  literature  that  has  appeared  on  the  subject 
of  the  striated  muscle,  no  account  apparently  exists  of  the  histo- 
genesis of  the  heart  muscle  of  the  chick.  This  seems  rather 
strange  in  face  of  the  fact  that  the  chick  always  has  been  the 
classic  subject  for  embryological  research.  The  present  study 
was  undertaken  for  the  purpose  of  determining  the  structures 
existing  in  the  heart  muscle  cell  of  the  chick,  especially  for  com- 
parison with  results  of  similar  work  that  has  already  been  done  on 
other  vertebrate  forms. 

The  particular  phase  of  the  histogenesis  treated  in  this  paper 
is  the  relation  between  the  cyto-reticulum  of  the  embryonic  cell 
and  the  fibril  bundles  as  found  in  the  adult  muscle  tissue.  To 
avoid  any  possible  confusion  or  misunderstanding,  a  definition  of 
terms  here  at  the  outset  will  perhaps  not  be  amiss. 

By  cyto-reticulum,  the  writer  means  the  deeply  staining  net- 
work found  traversing  the  cytoplasm  of  early  embryonic  cells. 
The  fibril  bundles,  corresponding  to  the  "Muskelsaulchen"  of 
Koelliker,  02,  are  the  striated  longitudinally  disposed  masses  run- 
ning the  length  of  the  adult  cell.  Each  fibril  bundle  is  composed 
of  more  elementary  parts  called  fibrils. 

On  account  of  the  abundance  of  material  and  the  ease  with 
which  the  various  stages  in  the  development  of  the  cell  can  be  se- 
cured, the  chick  is  very  well  adapted  to  a  study  of  this  kind.  The 
one  serious  objection  is  that  the  various  structures  of  the  cell 
are  not  as  well  differentiated  as  in  some  other  forms. 

To  Professor  Guyer,  at  whose  suggestion  this  work  was  taken 
up,  the  writer  is  much  indebted  for  valuable  assistance. 

*  From  the  American  Journal  of  Anatomy,  January,  1907. 

263 


264  DAN  BRIDGE   MEMORIAL 

METHODS. 

A  detailed  study  of  the  cytoplasmic  structures  of  the  heart 
muscle  cell  requires  the  use  of  a  very  high  magnification.  To 
secure  good  definition,  it  was  found  necessary  to  make  sections 
3  fx  in  thickness.  Sections  of  4  to  10  /a  thicknesses  were  used  for 
general  structure  and  form  of  the  cell.  Sections  were  cut  in 
paraffin. 

Of  the  different  fixing  agents  used,  none  gave  more  satisfac- 
tory preparations  than  Kolossow's,  92,  solution.  None  was  found 
to  surpass  it  in  faithful  preservation  and  differentiation  of  the 
cytoplasmic  structures.  The  tissue  is  killed  and  hardened  by 
treatment  for  15  minutes  with  a  1  per  cent,  osmic  acid  solution. 
This  is  followed  by  immersion  for  the  same  length  of  time  in  a 
reducing  mixture  of  pyrogallol  and  tannin.  The  tissue  is  next 
washed  in  a  0.25  per  cent,  solution  of  osmic  acid,  and  then  in 
water.  After  being  passed  through  graded  alcohols,  the  tissue  is 
cleared  in  xylol,  and  embedded  in  paraffin.  This  method  followed 
by  Delafield's  hematoxylin  or  methylene  blue,  counterstained  by 
0.5  per  cent,  solution  of  acid  fuchsin  in  70  per  cent,  solution  of 
alcohol  gave  excellent  results.  The  chromatin  structures  of  the 
nucleus  and  the  cyto-reticulum  appear  almost  black,  while  the  un- 
differentiated cytoplasm  is  red.  Acid  fuchsin  alone  without  the 
nuclear  stains  also  yields  good  preparations. 

One  objection  to  Kolossow's  solution  is  that  it  does  not  pene- 
trate rapidly  enough,  and  as  a  result,  especially  in  adult  tissue, 
the  structure  of  the  cells  in  the  interior  could  not  be  made  out  as 
well  as  that  of  those  in  the  peripheral  portions  of  sections. 

Another  killing  fluid  which  gave  good  results  was  Gilson's 
mercuro-nitric  fixing  mixture,  followed  by  iron  hematoxylin  for 
staining.  This  method  produces  more  uniformly  penetrated  prep- 
arations, but  does  not  show  the  cytoplasmic  reticulum  to  such 
good  advantage  as  the  osmic  acid  method. 

Hermann's  platino-aceto-osmic  mixture  was  also  tried.  After 
treatment  with  this  solution  the  tissue  is  stained  with  alcoholic 
safranin  for  24-28  hours.  The  preparation  is  then  treated  with 
gentian  violet  according  to  Gram's  method.  This  method  was 
not  as  satisfactory  as  either  of  the  foregoing. 

Picrosulphuric-acetic  acid  was  used  with  good  results  where 


W  I  E  M  A  N  265 

general  structure  was  the  object  sought.  This  fluid  is  made 
by  adding  a  5  per  cent,  solution  of  acetic  acid  to  Kleinenberg's 
picrosulphuric  acid  solution.  Treatment  with  the  above  is  fol- 
lowed by  staining  successively  with  carmalum  and  Delafield's 
hematoxylin. 

Besides  section  methods,  maceration  was  employed.  This  pro- 
cess was  used  with  satisfactory  results  in  studying  the  general 
structure  of  the  entire  cell  of  the  adult  tissue.  Of  the  various 
methods  tried,  treatment  for  twenty-four  hours  with  a  20  per 
cent,  solution  of  nitric  acid,  followed  by  staining  with  Delafield's 
hematoxylin  and  acid  fuchsin,  gave  the  best  preparations. 

THE  ADULT   HEART-MUSCLE  CELL. 

Examination  of  the  adult  tissue  shows  it  to  be  composed  of  an 
anastomosing  network  of  fibers,  the  demarcation  of  which  into 
cells  is  rather  uncertain.  Apparently  a  fiber  is  arranged  into  cyl- 
indrical cells  the  length  of  which  exceeds  many  times  the  diameter. 
The  tapered  ends  of  the  cells  seem  to  fit  together  much  in  the  man- 
ner of  a  dove-tailed  joint.  The  nucleus  is  oblong  in  shape  and 
occupies  a  more  or  less  central  position,  although  it  is  sometimes 
seen  very  close  to  the  periphery  of  the  fiber. 

The  contractile  substance,  the  fibril  bundles,  consists  of  deeply 
staining  longitudinal  masses  running  the  length  of  the  cell.  Sur- 
rounding the  fibril  bundles  and  separating  each  one  is  the  undif- 
ferentiated sarcoplasm.  The  fibril  bundles  are  divided  by  cross 
striations  at  right  angles  to  the  longitudinal  axis  into  alternating 
broad,  deeply  staining  bands,  and  narrower  bands  more  lightly 
stained.  The  broad,  heavily  stained  bands  correspond  to  the 
"Ouerscheibe,"  or  "Briicke's  doubly  refractive  substance"  of  mam- 
malian heart  muscle  (MacCallum,  97).  By  carefully  focusing 
up  and  down,  a  very  narrow,  deeply  staining  band  can  be  seen 
crossing  the  light  bands.  This  is  the  "Zwischenscheibe,"  or 
"Krause's  membrane,"  which  structure  is  not  very  distinct  nor 
readily  made  out.  The  continuation  of  this  line,  however,  can  be 
plainly  seen  in  the  sarcoplasm  surrounding  the  fibril  bundle.  The 
Querscheibe  are  slightly  larger  in  diameter  than  the  more  lightly 
stained  parts  between. 

The  sarcoplasm  surrounding  the  fibril  bundles  is  not  homo- 


266  DANDRIDGE  MEMORIAL 

geneous,  but  is  divided  into  disc-like  parts  which  could  be  es- 
pecially well  seen  in  peripheral  cells  when  partially  macerated. 
In  preparations  of  this  kind,  the  discs  were  found  separate  from 
each  other,  while  the  fibril  bundles  remained  intact,  that  is,  they 
did  not  break  up  into  corresponding  lengths.  This,  it  seems,- 
would  militate  against  the  idea  of  Krause's  membrane  being  con- 
tinuous with  the  line  of  demarcation  between  two  adjacent  sarco- 
plasmic discs.  If  the  latter  were  the  case,  it  would  seem  that  the 
fibril  bundles  should  show  a  tendency  to  break  and  separate  along 
the  line  of  Krause's  membrane.  This  did  not  happen.  Hence 
it  may  be  what  appears  to  be  Krause's  membrane  may  only  be  the 
line  of  demarcation  between  two  successive  sarcoplasmic  discs 
seen  through  the  lightly  staining  parts  of  the  fibril  bundles. 

Teased  tissue  showed  the  fibril  bundles  each  to  be  made  up  of 
smaller  longitudinally  disposed  parts,  the  fibrils.  The  fibril 
bundles  were  in  all  cases  surrounded  by  sarcoplasmic  discs. 

In  the  adult  tissue  the  fibril  bundles  are  more  abundant  in  the 
periphery  of  the  cell  than  toward  the  center,  which  is  composed 
for  the  most  part  of  a  network  of  undifferentiated  protoplasm. 
In  most  cases  the  cells  are  so  closely  applied  that  it  is  difficult 
to  distinguish  cell  walls.  These  sections  show  the  fibril  bundles 
as  dark,  deeply  staining  patches  surrounded  by  the  sarcoplasmic 
discs.  Some  of  these  discs  are  further  subdivided  into  what 
MacCallum,  97 ,  has  described  as  "small  sarcoplasmic  discs." 

Between  the  cells,  and  connecting  them,  may  be  noticed  a  num- 
ber of  threads,  which  resemble  very  much  the  strands  of  the 
reticular  structure  of  the  interior  of  the  cell.  Just  what  the  origin 
and  nature  of  these  structures  are  could  not  be  determined.  A 
study  of  these  structures  would  doubtless  throw  oome  light  on  the 
question  of  whether  the  heart  muscle  fiber  is  a  syncytium  or  not. 
No  structure  analogous  to  the  "protoplasmic  bridges"  of  mam- 
malian heart  tissue  or  the  "stratum  granulosum  terminale" 
(Prezwoski,  as  quoted  by  MacCallum,  97,  p.  611),  of  human 
heart  muscle,  was  found  connecting  the  ends  of  the  cells. 

Such,  in  brief,  are  the  structures  met  with  in  the  heart  muscle 
cell  of  the  adult  chick. 


W  I  E  M  A  N  267 

EMBRYONIC  DEVELOPMENT. 

To  study  the  different  stages  through  which  the  ceil  passes  in 
its  development,  sections  from  embryos  varying  in  length  from 
8  mm.  (15  somites),  to  22  mm.  (8  days),  were  examined.  Cells 
characterized  by  a  certain  structure  are  not  confined  to  any  one 
stage.  In  the  following  account  cells  are  said  to  belong  to  a 
certain  stage  because  they  were  first  noticed  in  that  stage,  al- 
though they  may  be,  and  frequently  are,  seen  in  sections  from 
tissue  several  days  older. 

Thirty  hours  (i^-soniite  stage). — Cells  of  this  stage  exhibit  in 
longitudinal  section  a  characteristic  short,  broad  cylindrical  form. 
The  ends  of  the  cell  taper  rather  abruptly  from  the  center.  The 
nucleus  is  large  and  oval ;  its  short  diameter  being  but  slightly 
less  than  the  diameter  of  the  cell.  Large  chromatin  masses  may 
be  seen  as  heavily  stamed,  irregularly  shaped  clumps,  and  a  very 
fine  network  traverses  the  nucleus. 

The  cytoplasm  exhibits  a  pronounced  reticular  structure,  with 
large  and  irregular  meshes.  At  the  intersections  of  the  threads 
of  this  network,  the  staining  is  somewhat  heavier,  marking  off 
these  parts  more  distinctly  than  the  rest  of  the  reticulum. 

Cells  of  this  general  description  are  typical  of  the  heart  tissue 
in  its  very  earliest  state  of  formation.  They  can  be  readily  dis- 
tinguished from  the  unmodified  mesenchyme  cells,  in  that  they 
do  not  show  the  branched  structure  of  the  latter. 

Seventy-tzvo  hours  {3-day  stage). — Up  to  this  period  in  its  de- 
velopment, the  cell  differs  but  slightly  from  the  description  given 
above.  At  this  time,  however,  several  changes  are  to  be  noticed. 
The  cell  has  become  larger  and  the  tapering  ends  have  increased 
in  length.  The  points  of  intersection  of  the  threads  of  the  cyto- 
reticulum  are  more  distinctly  marked  than  before  by  accumula- 
tions of  heavily  staining  material,  spherical  in  form.  These  are 
also  shown  in  cross  sections.  The  nucleus  is  oval  in  form  though 
somewhat  smaller  than  in  earlier  stages.  The  chromatin  masses 
have  decreased  in  size. 

Ninety-six  hours  (4-day  stage). — The  cell  has  increased  enor- 
mously in  size,  especially  in  its  longer  diameter.  The  deposits  on 
the  cyto-reticulum  are  larger  and  stand  out  very  clearly  and  dis- 
tinctly.   The  meshes  of  the  cyto-reticulum  are  still  very  irregular 


268  DANDRIDGE  MEMORIAL 

in  form.  The  nucleus  does  not  seem  to  have  undergone  the  same 
increase  as  the  cytoplasm,  and  its  chromatin  masses  have  become 
smaller  and  more  evenly  distributed.  Some  of  the  meshes  of  the 
cytoplasmic  network  are  divided  into  smaller  parts,  the  small 
sarcoplasmic  discs  of  MacCallum,  97. 

1 20- 1^0- hours'  stage. — The  cyto-reticulum  has  undergone  a 
striking  change.  Instead  of  the  irregular  structure  of  the  pre- 
ceding stages,  we  find  a  definite  arrangement  of  the  network  into 
rectangular  meshes.  The  deposits  on  the  reticulum  have  increased 
in  bulk  in  such  a  way  that  in  longitudinal  section  they  appear  as 
oval-shaped  bodies. 

This  re-arrangement  of  the  meshwork  is  apparently  the  first 
step  in  the  laying  down  of  the  fibril  bundles.  Subsequent  de- 
velopment shows  that  the  longitudinal  strands  bearing  the  deposits 
represent  the  axes  of  the  fibril  bundles,  and  the  deposits,  the 
Querscheibe  of  the  adult  tissue.  The  transverse  threads,  accord- 
ing to  MacCallum,  98,  give  rise  (in  the  mammal)  to  Krause's 
membrane.    However,  this  will  be  referred  to  again  later. 

Cross  sections  show  the  meshes  of  the  reticulum  to  be  further 
subdivided,  but  few  of  the  original  size  remaining.  It  is  to  be 
noted  that  one  or  two  very  large,  irregularly  shaped  meshes  are 
present  in  this  section.  Apparently  these  areas,  in  later  stages, 
become  divided  into  smaller  parts,  just  as  the  neighboring  cyto- 
plasm has  already  become  divided.  Evidently  this  is  the  manner 
in  which  the  growth  process  in  the  cell  takes  place,  the  cytoplasm 
in  the  smaller  meshes  increasing  greatly  in  bulk  and  then,  by  sub- 
division, producing  a  number  of  meshes  approximately  the  size 
of  the  first. 

The  nucleus  is  oblong  in  longitudinal  section,  and  roughly  cir- 
cular in  cross  section.  The  chromatin  masses  are  usually  small. 
It  appears  that  Eycleshymer,  04,  in  his  work  on  skeletal  muscle- 
cells  of  Necturus,  found  just  the  opposite  change  to  take  place  in 
the  size  and  distribution  of  the  chromatin  gi-anules,  i.  c,  in 
younger  stages  the  karyosomes  were  evenly  distributed  in  the 
nucleus,  and  in  later  stages  collected  in  large  masses. 

1^0-140-hours'  stage. — The  most  interesting  phase  of  the  entire 
development  is  seen  at  this  period.  The  evidence  met  with  in  this 
stage  furnishes  the  most  decisive  proof  in  favor  of  a  definite 


W  I  E  ^I  A  N 


269 


relationship  existing  between  the  cyto-reticulum  of  the  embryonic 
cell  and  the  fibril  bundles  of  the  adult.  Longitudinal  sections 
present  a  very  marked  appearance  of  cross  striations.  On  ex- 
amination it  is  found  that  these  striations  are  produced  by  a 
growth,  principally  in  length,  of  the  deposits  on  the  cyto-reticulum 
of  previous  stages.  These  heavily-stained  bands  stand  out  as 
clearly  as  if  stamped  with  a  die.  Sections  at  this  period  present 
all  gradations  of  striations  as  may  be  seen.  The  transverse 
strands  of  the  cyto-reticulum  are  not  very  prominent.  The  taper- 
ing ends  of  the  cells  show  an  enormous  increase  in  length.  It  is 
to  be  noted  that  the  striations  first  appear  in  the  elongated  ends, 
at  least  they  show  a  greater  degree  of  development  in  this  part  of 
the  cell.    These  markings  cause  the  ends  of  the  cell  to  stand  out 


more  prominently  than  the  other  regions,  and  it  is  now  very 
difficult  to  distinguish  cell  walls  in  longitudinal  sections.  How- 
ever, by  means  of  the  heavy  striations,  one  can  see  how  these 
slender  projecting  ends  have  made  their  way  between  other  cells, 
and  thus  trace  the  formation  of  the  syncytium-like  structure  of 
the  adult  tissue.  In  the  later  stages,  when  the  cell  exhibits 
uniform  striation,  the  course  of  the  ends  of  the  cells  cannot  be 
so  well  followed.  The  accompanying  diagram  would  then  repre- 
sent the  structure  of  the  adult  fiber  in  longitudinal  section.  This 
would  also  explain  the  fact  that  a  cross  section  of  the  adult 
tissue,  as  for  example,  from  a  to  b,  shows  cells  of  widely  varying 
diameter.  A  similar  explanation  was  offered  by  MacCallum,  98, 
in  the  case  of  the  striated  muscle  of  the  pig. 

Cross  sections  show  an  increased  number  of  the  smaller  meshes 
of  the  cyto-reticulum,  while  the  deeply  staining  deposits  which 
are  cross  sections  of  fibril  bundles  have  become  greatly  enlarged. 


270  DANDRIDGE  MEMORIAL 

These  heavily  staining  patches  are  best  developed  toward  the 
periphery  of  the  cell.    The  nucleus  is  roughly  oval  in  outline. 

From  this  structure  to  that  of  the  adult  is  but  a  step.  While 
all  the  intermediate  stages  between  this  and  the  adult  were  not 
examined,  sections  from  stages  beyond  this  up  to  the  eighth  day, 
showed  the  same  structure  in  various  degrees  of  development. 
In  the  adult  the  sarcoplasmic  discs  are  better  developed.  The 
Querscheibe  are  broader  and  resemble  thick,  flat  plates.  The 
length  and  diameter  of  the  cell  is  greatly  increased. 

SUMMARY. 

The  facts  which  appear  to  be  of  importance  as  set  forth  in  the 
foregoing,  are  as  follows : 

1.  The  cytoplasm  of  the  early  embryonic  heart  cell  is  traversed 
by  an  irregular  network,  the  nodes  of  which  are  marked  by  heavily 
staining  deposits. 

2.  This  network  tends  to  become  more  and  more  regular,  until 
its  strands  are  longitudinally  and  transversely  disposed. 

3.  The  heavily  staining  deposits  on  the  primitive  network  de- 
velop into  the  Querscheibe  of  the  adult  fibril  bundle. 

4.  The  longitudinally  disposed  lines  of  the  network  represent 
the  axes  of  the  fibril  bundles  of  the  adult. 

5.  The  sarcoplasmic  discs  of  the  adult  develop  from  the  inter- 
reticular  cytoplasm  of  the  embryonic  cell. 

GENERAL  DISCUSSION  ON  THE  RELATION  BETWEEN  THE  CYTOPLASM 
AND  THE  FIBRIL  BUNDLES. 

According  to  Ranvier,  89,  the  myocardium  of  the  mammal  is 
composed  of  rhomboidal  branching  cells.  The  nucleus  is  cen- 
trally placed  and  is  surrounded  by  a  granular  mass  stretching  out 
in  the  axis  of  the  cell.  Surrounding  this  granular  mass  is  the 
contractile  element  which  shows  longitudinal  and  transverse 
markings.  This  element  is  the  fibril  and  is  made  up  of  successive 
segments  having  the  same  structure  as  voluntary  muscle. 

Koelliker,  02,  describes  the  mammalian  heart  muscle  as  com- 
posed of  an  interlacing  network  of  cells  having  centrally  placed 
nuclei.    The  contractile  substance,  as  in  voluntary  muscle,  consists 


W  I  E  M  A  N  271 

of  fibril  bundles,  the  so-called  "Muskelsaulchen,"  which  show  a 
definite  transverse  striping. 

Of  the  later  workers,  Godlewski's,  02,  description  is  interesting, 
because  of  his  denial  of  cell  structures  in  the  heart  muscle  of  the 
rabbit.  According  to  him  the  heart  muscle  is  a  syncytium  in 
which  there  is  no  cell  demarcation.  The  contractile  substance  is 
the  fibril  which  shows  the  various  markings  described  by  other 
authors. 

Thus,  in  general,  in  addition  to  the  above,  the  work  of  investi- 
gators goes  to  show  that  the  contractile  substance  in  the  muscle 
tissue  is  the  fibril.  A  number  of  these  in  turn  compose  the  fibril 
bundle.  Workers  are  not  agreed  as  to  the  origin  of  the  fibril 
bundles.  The  older  hypothesis  that  they  are  extra-cellular  struc- 
tures is  now  refuted,  and  the  generally  accepted  opinion  is  that 
they  are  intracellular. 

Two  current  views  exist  as  to  the  nature  of  the  fibril  bundles. 
The  first  is  that  these  structures  are  coagulation  products,  and 
that  the  living  cell  contains  neither  cyto-reticulum  nor  fibrils 
(Englemann,  73-81),  The  second  view  is  that  the  fibrils  are 
differentiated  structures  which  are  formed  in  the  living  cell.  The 
latter  theory  is  the  one  which  the  results  of  many  workers  seem 
to  verify.  Of  the  latest  workers  Eycleshymer,  04,  reports  having 
observed  the  fibrillse  (fibrils)  in  the  living  muscle  cells  of  larval 
necturus. 

Concerning  the  origin  of  the  fibrils,  there  are  what  is  known  as 
the  network  theory  and  the  fibrillar  theory.  The  upholders  of  the 
network  theory  maintain  that  the  muscle  cell  contains  a  con- 
tractile reticulum,  the  longitudinal  threads  of  v/hich  form  the 
fibrils,  the  meshes  being  filled  with  a  more  fluid  substance.  Others 
consider  that  the  fibrils  are  produced  by  the  coagulation  of  the 
fluid  substance,  as  a  result  of  the  action  of  various  reagents. 
Later  work  apparently  refutes  the  latter  idea.  The  advocates  of 
the  fibrillar  theory  maintain  that  the  fibrils  are  the  contractile 
elements,  and  further,  that  they  arise  independently  of  the  cyto- 
reticulum.  Eycleshymer's,  04,  work  on  necturus,  supports  this 
idea,  and  Godlewski,  02,  in  his  work  on  the  striated  muscle  cell 
of  the  rabbit,  has  been  able  to  find  no  trace  of  a  cytoplasmic 
network. 


272  DANDRIDGE   MEMORIAL 

In  the  theory  urged  by  AlacCallum,  98,  we  have  a  combination 
of  the  network  and  the  fibrillar  theories.  In  this  author's  words 
(p.  211),  "It  simplifies  the  conception  of  the  structure  of  striated 
muscle  fiber  greatly,  to  consider  the  fibril  bundles  and  the  mem- 
branes bounding  the  compartments  in  the  sarcoplasm  as  derived 
from  the  primitive  network  found  in  the  muscle  cells  of  very 
young  embryos."  (p.  209)  "This  network  tends  to  become  more 
and  more  regular  until  the  meshes  are  of  the  form  of  large  discs. 
Some  of  these  break  up  into  smaller  ones  and  in  the  nodal  points 
of  the  network  there  is  an  accumulation  or  differentiation  of  its 
substance,  giving  rise  to  longitudinally  disposed  masses.  These 
become  what  in  the  adult  are  known  as  fibril  bundles  and  the 
discs  are  the  sarcoplasmic  discs." 

Now  the  question  is.  How  do  these  theories  apply  to  the  con- 
ditions met  with  in  the  heart  muscle  of  the  chick?  We  will 
consider  JMacCallum's  theory  first. 

The  occurrence  of  the  breaking  up  of  the  meshes  of  the  c}^o- 
reticulum  into  smaller  parts  was  noticed  in  the  case  of  the  chick. 
That  the  fibril  bundles  arise  from  the  center  of  the  meshes  at  the 
nodal  points  of  the  network  appears,  however,  to  be  untrue.  Here, 
in  fact,  it  seems  that  the  nodes  of  the  original  network  mark  the 
positions  of  the  fibril  bundles ;  in  other  words,  that  the  primitive 
longitudinal  threads  develop  into  these  structures.  To  illustrate, 
the  accompanying  figure  represents  a  diagrammatic  cross-section 
of  the  cyto-reticulum.  The  unbroken  lines  represent  the  threads 
of  the  original  network.  The  circular  masses  at  the  intersections 
of  this  network  (a-,  b,  c,  etc.)  represent  the  heavily-stained  de- 
posits. The  dotted  lines  divide  the  large  meshes  or  discs  into  the 
"small  sarcoplasmic  discs"  of  MacCallum  {boc,  cod,  etc.).  Now 
according  to  the  author  just  mentioned,  a  fibril  bundle  arises  in 
the  center  of  any  large  disc  at  the  point  of  intersection  of  the 
dotted  lines  {o,  x,  etc.).  The  full  lines  would  then  represent 
boundaries  of  sarcoplasmic  discs.  However,  in  the  case  of  the 
chick  the  facts  seem  to  indicate  that  the  fibril  bundles  arise  at  the 
points  of  intersection  of  the  lines  of  the  original  network  (a,  e,  b, 
etc.).  Then  the  sarcoplasmic  disc  surrounding  any  one  particular 
fibril  bundle,  as,  for  example,  that  one  the  cross  section  of  which 
is  represented  by  a,  would  be  the  area  bounded  by  yboexrzk. 


W  I  E  M  A  N  273 

The  writer's  preparations  clearly  show  that  the  nodal  points  of 
the  original  cyto-reticulum  of  the  embryonic  heart  cell  are  marked 
by  more  heavily  staining  deposits,  both  in  longitudinal  and  in 
cross  section.  The  deposits  can  be  followed  in  successive  stages, 
and  are  always  identified  with  the  longitudinal  and  transverse 
threads  of  the  network.  Eventually  they  develop  into  the  Quer- 
scheibe,  and  the  longitudinal  threads  of  the  network  become  the 
axes  of  the  fibril  bundles  of  the  adult  tissue.  If  this  be  true,  the 
fibril  bundles  cannot  originate  from  the  centers  of  the  meshes 
seen  in  cross  sections  of  the  cyto-reticulum. 

Suppose  now  that  fibril  bundles  were  to  form  at  the  points  a 
and  e  of  the  diagram.    Then  we  would  have  the  two  fibril  bundles 


surrounded  by  one  set  of  sarcoplasmic  discs  (odtpxrzkyb),  a 
condition  sometimes  found  in  the  adult ;  also  mentioned  by  Mac- 
Callum,  97,  (p.  613),  in  the  human  heart  muscle.  However,  were 
these  two  sets  of  sarcoplasmic  discs  to  become  separated  by  a 
plane  of  division  along  a  line  from  o  to  x,  then  each  fibril  bundle 
would  have  its  ow^i  set  of  sarcoplasmic  discs,  the  structure  more 
generally  met  with  in  the  adult. 

If  the  fibril  bundle  in  its  development  follows  the  method  sug- 
gested by  the  w^riter,  another  difficulty  is  encountered  with  the 
results  of  MacCallum's,  98,  work.  This  worker  states  that  the 
transverse  membranes  of  the  cytoplasmic  reticulum  of  the  myo- 
blasts of  man  and  of  pig  give  rise  to  Krause's  membrane  in  the 


274  DAX  BRIDGE   MEMORIAL 

adult.  Attention  is  called  to  the  fact  that  the  intersections  of 
these  transverse  lines  with  the  longitudinal  lines  of  the  reticulum 
mark  the  positions  of  the  deeply-stainiiig  substance  which  later 
becomes  the  Querscheibe.  Now,  in  the  adult,  Krause's  membrane 
is  found  as  a  narrow  transverse  band  across  the  lightly-staining 
portions  of  the  fibril  bundles,  and  not  at  all  connected  with  the 
Querscheibe.  Thus  it  is  readily  seen  that  IMacCallum's  explana- 
tion of  the  formation  of  this  structure  does  not  apply  in  the  case 
of  the  chick,  nor  could  its  origin  be  determined  satisfactorily,  for, 
as  was  remarked  in  another  place,  it  is  not  very  well  differentiated 
in  the  heart'  muscle  of  the  adult  chick. 

At  this  point  it  is  interesting  to  consider  the  work  of  Eycle- 
shymer,  04,  on  the  striated  muscle  cell  of  Necturus.  This  author 
states  that  in  the  study  of  the  striated  muscle  cells  of  Necturus, 
he  has  been  unable  to  find  any  evidence  of  a  definite  or  fixed  re- 
lation between  the  cytoplasmic  network  and  the  fibrillas  (fibrils). 
Further,  as  serious  objection  to  the  existence  of  such  a  relation, 
he  says  that  the  fibrillse  are  unstriated  for  some  time  after  their 
appearance. 

In  the  case  of  the  chick,  however,  the  above  is  not  true.  For 
if  we  consider  the  longitudinal  threads  of  the  network  as  the 
incipient  fibril  bundles,  then  the  deposits  marking  the  intersections 
of  the  threads  would  represent  the  striations,  since  later  these 
develop  into  the  Querscheibe  of  the  adult  tissue.  The  question 
is  just  what  is  to  be  understood  by  "first  appearance  of  fibrillse." 
If  by  this  we  mean  the  earliest  stage  in  the  development  of  the 
fibril  bundles  at  which  there  is  any  resemblance  to  the  adult 
structure,  we  may  say  that  the  fibrillse  are  striated  from  the  start 
in  the  chick. 

With  reference  to  another  point  in  this  connection,  the  writer 
here  quotes  a  passage  from  the  same  author,  pp.  298,  299:  "A 
point  of  capital  importance  is  found  in  the  fact  that  in  Necturus, 
Amia,  Lepidosteus  ....  as  my  own  observations  show,  and 
in  other  forms  as  Kaestner,  92,  has  found,  the  beginning  of  fibril- 
lation is  coincident  with  the  first  contractions.  The  movements 
of  the  embryo  first  begin  in  the  anterior  of  the  mid-dorsal  myo- 
tomes and  in  these  the  myoblasts  are  first  fibrillated.  The  above 
considerations  led  the  writer  to  support  the  theory  that  the  fibrillae 


W  I  E  AI  A  X  275 

are  pre-existent  structures  and  represent  the  principal  contractile 
element." 

The  same  argument  cannot  be  applied  to  the  heart  muscle  of 
the  chick,  because  the  first  contractions  occur  at  the  time  when 
about  15-17  myotomes  have  been  formed  in  the  embryo.  As  may 
be  seen  from  the  representation  of  the  heart  muscle  cell  at  this 
stage,  no  structure  which  might  be  truly  called  a  fibril  is  present. 
The  first  appearance  of  anything  that  in  the  faintest  way  re- 
sembles the  adult  is  not  seen  before  the  120-130  hours'  stage. 

If  the  fibrillae  are  not  pre-existent  structures,  what  then  are  the 
contractile  elements  in  the  very  early  embryonic  stages  ?  In  view 
of  the  above  facts  the  explanation  offered  by  MacCallum,  97  (p. 
620),  seems  plausible.  The  author  suggests  that  the  contractile 
elements  in  the  early  embryonic  heart  would  be  represented  by  the 
irregular  network  seen  at  that  stage  before  true  fibrils  exist. 
This,  it  seems,  would  lend  support  to  the  writer's  suggestion  in 
regard  to  the  origin  of  fibrils.  For  if,  as  ]\IacCallum  says,  the 
cytoplasmic  network  represents  the  contractile  element  in  the 
early  stages,  it  seems  reasonable  at  least  to  consider  the  longi- 
tudinal lines  of  this  network  as  developing  into  the  fibrils  rather 
than  to  suppose  the  latter  to  arise  from  accumulations  of  the 
network-substance  in  the  cytoplasm  contained  between  the  meshes. 

In  conclusion,  the  results  of  the  work  embodied  in  this  paper 
point  to  the  existence  of  a  definite  relationship  between  the  c}lo- 
plasmic  reticulum  of  the  early  embryonic  cell  and  the  fibril  bun- 
dles of  the  adult  cell. 

REFERENCES. 

Engelmann,  Th.  W.,  73-81 :  !Mikroskopische  Untersuchurigen  iiber  die 
quergestreiften  IMuskelsubstanz.  I  u.  H  Pfliiger's  Arch.,  Bd.  vii,  1873. 
Kontraktilitat  und  Doppelbrechung.  Pfliiger's  Arch.,  Bd.  xi.  Xeue  Unter- 
suchungen  iiber  die  mikroskopischen  Vorgange  bei  der  Muskelkontraktion. 
Pfliiger's  Arch.,  Bd.  xviii,  1878.  Alikrometrische  Untersuchungen  an  kon- 
trahierten  Muskelfasern.  Pfliiger's  Arch.,  Bd.  26,  1881.  Bemerkungen  zu 
einen  Aufsatz  von  Fr.  Merkel :  Ueber  die  kontraktion  der  quergestreiften 
Muskelfaser.  Pfliiger's  Arch.,  Bd.  26,  1881.  Ueber  den  faserigen  Ban  der 
kontraktilen  Substanz  mit  besonderer  Beriicksichtigung  der  glatten  und 
doppelt  schrag  gestreiften  Muskelfasern.     Pfliiger's  Arch.,  Bd.  25,  1881. 

Eyclesh>Tner,  A.  C,  '04:  The  Cytoplasmic  and  Nuclear  Changes  in  the 
Striated  Muscle  Cell  of  Xecturus.    Am.  Journ.  Anat.,  Vol.  iii,  No.  3. 

Godlewski,  E..  '02:  Die  Entwickelung  des  Skelet-  und  Herzmuskelge- 
•\vebe  der  Saugethiere.     Arch.  f.  mikr.  Anat.,  Bonn,  1902,  Bd.  Ix. 

Koelliker,  "02:  Handbuch  der  Gewebelehre  des  Menschen.  6  Anlage, 
p.  609,  Leipz.,  1902. 


276  DAN  DRIDGE   MEMORIAL 

Kolossow,  A.,  '92:  Ueber  eine  neue  Methode  der  Bearbeitung  der  Ge- 
webe  mit  Osmiumsaure.  Zeitschr.  f.  wissenschaftl.  ]\likroskopie,  Bd.  9, 
1892,  p.  38. 

MacCallum,  J.  B.,  '97:  On  the  Histology  and  Histogenesis  of  the  Heart 
Muscle  Cell.  Anat.  Anz.,  Jena,  1897,  Bd.  xiii,  S.  609-620.  '98:  On  the 
Histogenesis  of  the  Striated  Muscle  Fiber  and  the  Growth  of  the  Human 
Sartorius  Muscle.  Johns  Hopkins  Hosp.  Bull.,  Baltimore,  1898,  Vol.  ix, 
pp.  208-215. 

Ranvier,  '89:  Traite  technique  d'histologie.     Paris,  1889. 


A   METHOD   OF   DEMONSTRATING   SPIROCPI^T^ 
AND  TRYPANOSOMES  BY  MEANS  OF  NIGROSIN.* 


BY  CHARLES  GOOSMANN,   M.D. 


BuRRi's  India  ink  method,  first  applied  to  the  diagnosis  of 
syphilis  by  Hecht  and  Wilenko/  has  received  considerable  favor 
on  account  of  its  simplicity.  There  is,  however,  some  evidence 
of  dissatisfaction  because  of  the  granularity  of  smears  made 
according  to  this  method.  Barach-  speaks  of  deceptive,  wavy 
fibres  resembling  spirochajta  forms  found  by  him  in  India  ink. 
Gins^  insists  on  thorough  sedimentation  of  the  ink,  and  also  ad- 
vises the  use  of  a  specially  prepared  glass  slide  to  facilitate 
making  thin  smears.  To  overcome  the  undesirable  granularity 
I  have  been  using  a  solution  of  nigrosin  (nigrosin  No.  699  of  the 
National  Aniline  and  Chemical  Co.,  Chicago),  which  gives  a  much 
smoother  background  than  India  ink.  This  is  a  blue-black  pig- 
ment, but  their  black  nigrosin  No.  15502  can  also  be  used.  Grueb- 
ler's  water-soluble  nigrosin  has  been  tried,  but  precipitates  too 
easily,  probably  on  account  of  its  greater  purity,  as  it  is  well 
known  that  impure  colloids  frequently  remain  in  solution  better 
than  the  purified.  The  nigrosin  recommended  above  can  be  ob- 
tained through  any  wholesale  druggist. 

With  coarse  spiroch?et«,  granularit}-  of  the  background  is 
immaterial.  With  more  minute  forms,  it  is  a  distinct  disadvan- 
tage, as  the  film  cannot  be  thinner  than  the  average  diameter  of 
the  granules,  and  if  the  film  is  thicker  than  the  organisms,  it  will 
blur  the  latter's  outlines.  In  the  demonstration  of  bacterial  fla- 
gella,  therefore,  the  India  ink  method  has  been  unsatisfactory,  as 
Gins,*  who  has  done  considerable  work  on  flagella,  admits. 

Attempts  to  show  flagella  on  Bacillus  typhosus,  however,  have 
not  been  successful,  probably  because  the  nigrosin  particles, 
though  much  smaller  than  India  ink,  are  still  too  large.    Nigrosin 

*  Reprinted  from  the  Journal  of  Cutaneous  Diseases,  Including  Syph- 
ilis, for  December,  1911. 

277 


278  DANDRIDGE  MEMORIAL 

is  a  suspension  colloid,  and  by  dark-ground  illumination  the 
minute  particles  of  which  it  is  composed  can  be  distinctly  seen. 
It  may  be  that  a  pigment  that  actually  enters  into  true  solution 
will  be  capable  of  rendering  these  minute  flagella  visible.  To 
illustrate  my  meaning:  Burri  describes  the  appearance  of  India 
ink  preparations  as  resembling  that  produced  by  dropping  pieces 
of  glass  rods  into  melted  dark-stained  agar  in  a  Petri  dish,  and 
when  the  agar  has  set,  holding  the  dish  to  the  light.  I  would 
modify  that  slightly.  The  India  ink  method  would  be  illustrated 
by  coloring  the  agar  with  large  irregularly  shaped  carbon  particles, 
as  large  as  the  diameter  of  the  thickest  piece  of  glass  rod.  The 
nigrosin  method  would  be  analogous  to  using  much  smaller  par- 
ticles to  color  the  agar,  permitting  the  production  of  a  thinner 
film,  and  rendering  visible  a  thinner  glass  rod.  If,  now,  we 
stained  the  agar  with  a  soluble  (i.e.,  non-granular)  dye,  we  might 
get  a  still  thinner  film,  and  sufficient  contrast  to  render  visible  a 
fine  thread  of  glass. 

The  preparation  of  the  nigrosin  is  very  simple.  Shake  up  an 
excess  of  the  nigrosin  with  distilled  water,  and  allow  it  to  settle. 
The  upper  stratum  can  then  be  pipetted,  or  carefully  decanted ; 
or,  as  I  prefer,  the  preparation  can  be  used  without  decanting, 
but  always  observing  caution  in  handling,  so  as  not  to  stir  up  the 
sediment.  It  is  well  to  avoid  contamination  of  all  sorts,  as  there 
is  a  tendency  for  the  nigrosin  to  become  more  coarsely  granular. 
Rod-shaped  pieces  of  nigrosin  occur,  but  these  can  cause  no  con- 
fusion with  bacteria,  because  bacteria  never  take  up  the  stain — 
therefore  always  appearing  uncolored. 

In  preparing  a  slide,  the  same  technique  is  used  as  with  India 
ink.  To  get  a  thin  smear  for  small  bacteria,  a  platinum  loopful 
of  the  material  to  be  examined  is  mixed  on  the  slide  with  less 
than  a  loopful  of  nigrosin  solution,  and  spread  with  the  edge  of 
another  slide  to  a  pale-blue  film.  The  slide,  of  course,  must  be 
clean.  A  convenient  way  to  avoid  the  use  of  too  much  nigrosin 
is  to  touch  the  loaded  platinum  loop  to  a  corner  of  the  slide, 
depositing  all  excess  and  mixing  the  remainder  with  the  material 
to  be  examined.  In  examining  blood  or  feces,  it  is  better  to 
dilute  with  normal  salt  solution  or  distilled  water  before  adding 
nigrosin,  in  order  to  separate  the  individual  particles.     For  thick 


G  O  O  S  ^I  A  N  N  279 

films,  such  as  are  best  for  large  organisms  (trypanosomes),  it  is 
sometimes  well  to  use  an  excess  of  nigrosin  solution.  After  the 
film  is  dry  the  oil  immersion  objective  can  be  used  directly,  or 
balsam  and  cover  glass  added.  My  preparations  have  shown  no 
deterioration  in  ten  months.  The  nigrosin  fluid  should  be  thick 
and  of  an  oily  consistence.  I  have  kept  such  a  solution  for  nine 
months  without  noticing  any  change  in  its  usefulness. 

It  would  be  a  distinct  advantage  if  the  living  and  motile  trepo- 
nema  could  be  seen  without  resorting  to  the  dark-field  illumination 
as  generally  obtained.  Meirowski^^  has  stained  living  spirochsetre 
with  various  stains,  but  the  organisms  lose  their  motility  in  a  few 
minutes.  In  1888,  Certes^  had  obtained  a  dark  background  for 
the  study  of  living  infusoria  by  the  addition  of  aniline  black. 
Faber-Domergue,®  in  1889,  had  used  diphenylamin  blue  for  the 
same  purpose.  Shortly  after  Hecht  and  Wilenko  published  their 
results  with  India  ink,  I  tried  to  find  a  method  which  would  have 
the  simplicity  of  their  technique  and  yet  retain  the  motiHty  of  the 
organisms.  Neither  pure  aniline  black  nor  diphenylamin  blue 
were  at  all  suitable  for  spirochsetse  or  trypanosomes,  however, 
because  the  pigments  were  precipitated  by  the  tissue  fluids.  The 
nigrosin  mentioned  above  (nigrosin  No.  699)  did  not  precipitate 
and  was  an  improvement  on  India  ink  for  dry  smears.  It  was 
very  toxic  to  spirochsetse,  however,  possibly  due  to  the  presence 
of  arsenic.  Further  experiments  with  purified  aniline  pigments 
will  be  necessary  before  it  can  be  decided  whether  living  and 
motile  spirochastae  will  be  rendered  visible  by  this  method.  Tryp- 
anosomes lemain  alive  twenty-four  hours  in  nigrosin  solutions, 
and  bacteria  seem  to  retain  their  motility  for  a  long  time.  In  fact, 
the  marked  susceptibility  of  spirochaetae,  whether  from  syphilis 
or  the  normal  mouth,  to  the  toxic  action  of  nigrosin,  seemed 
interesting  from  a  biologic  standpoint. 

The  following  extracts  from  various  writers  show  the  most 
important  points  in  differentiating  between  the  S pirochccta  den- 
tium  and  the  Treponema  pallidum.  Hoffmann^  says  that  the 
Spirochceta  dentium  is  thicker  in  relation  to  length,  therefore  more 
plump  appearing,  the  thin  ones  being  mostly  shorter  than  the 
Treponema  pallidum.  The  ends  of  the  Spirochccta  dentium  are 
more  blunt;    flagella-like  terminations  are  less  common.       The 


280  DAN  DRIDGE   MEMORIAL 

spirals  of  the  Spirochcuta  dentium  are  flatter,  less  regular  and 
narrower. 

Plaut^  says  that  the  SplrocJueta  dentium  is  almost  always 
shorter  than  the  organism  of  syphilis.  It  is  generally  straight, 
and  thicker  than  the  Treponema  pallidum.  The  windings  are 
very  close  in  the  Spirochcuta  dentium. 

Gurd"  says  the  Spirochceta  dentium  is  always  thicker  than  the 
Treponema  pallidum.  The  extremities  of  the  former  are  not 
drawn  out  in  the  manner  of  the  latter.  It  never  has  more  than 
five  turns  to  the  diameter  of  a  red  blood  cell,  while  the  organism 
of  syphilis  has  six  or  seven.  It  is  also  shorter  than  the  treponema. 

Park  and  Williams^  say  that  the  SpirodJiccta  dentium  is  some- 
what shorter  and  thicker.  It  does  not  terminate  in  flagella-like 
ends.  The  spirals  are  1.0  micron  long  and  0.5  micron  deep;  while 
the  spirals  of  the  Treponema  pallidum  are  1.0  micron  long  and 
1.0  to  1.5  micron  deep.  Discussing  the  preceding  differential  fea- 
tures, one  at  a  time,  we  have : 

(a)  The  Spirochceta  dentium  is  shorter  and  thicker  than  the 
Treponema  pallidum.  ]Many  short  forms  of  the  latter  are  found, 
especially  in  preparations  made  from  fresh  secretions.  Greater 
thickness  is  hardly  confirmed  by  the  photomicrographs  or  by 
visual  observations.  It  is  not  at  all  unlikely,  however,  that  varia- 
tions in  size  do  occur  in  all  these  forms.  Gerber^-  makes  two 
*forms  out  of  the  Spirochceta  dentium^  the  large  ones,  for  which  he 
retains  the  above  name,  and  a  smaller  form,  which  he  calls  the 
Spirochceta  denticola. 

(b)  The  ends  of  the  Spirochceta  dentium  are  more  blunt; 
flagella-like  ends  are  less  common  than  in  the  Treponema  palli- 
dum. This  may  be  true  in  stained  specimens,  but  India  ink  or 
nigrosin  preparations  do  not  show  any  such  distinction. 

(c)  The  spirals  of  the  Spirochcuta  dentium  are  flatter,  less 
regular  and  narrower.  No  difference  in  regularity  could  be  ob- 
served in  my  specimens.  The  spirals  of  the  Spirochceta  dentium 
seem  very  slightly  flatter.  To  confirm  this  point,  I  used  a  low- 
power  (two  inch)  objective  and  micrometer  eyepiece  on  the 
specimens  prepared  for  this  article,  but  instead  of  the  ratio  of 
length  to  height  given  by  Park  and  Williams  (vide  supra)  the 
following  ratio  was  found:  The  length  of  the  turns  of  the  Spiro- 


GOOS^IAXX  281 

cli<rta  doitiiiiii  were  to  their  height  as  1:0.5;  but  the  length  of 
the  turns  of  the  Treponema  pallidum  were  to  their  height  as 
1 :0.75.  In  other  words,  even  in  the  Treponema  pallidum,  the 
turns  were  not  as  high  as  long,  instead  of  being  1  to  1.5  times  as 
high.  This  merely  illustrates  the  narrow  margin  for  differentia- 
tion. Any  distinction  that  rests  on  such  slight  variations  in  size 
is  unreliable  in  practice.  Gurd's  distinction,  that  the  Spirochccta 
dentiitm  never  has  more  than  five  turns  to  the  diameter  of  a  red 
blood  cell,  while  the  treponema  has  six  or  seven,  would  indicate 
that  he  believes  that  the  turns  of  the  former  are  further  apart 
than  in  the  latter;  all  the  other  writers  quoted  above  give  nar- 
rower turns  to  the  same  organism. 

Levaditi  and  Alclntosh^'^  have  been  able  to  find  forms  of  Trepo- 
nema pallidum  that  could  not  be  distinguished  from  the  Spiro- 
chccta dcntium;  Gerber^-  also  considers  the  differentiation  im- 
possible in  many  cases,  and  admits  that  he  has  not  been  able  to 
find  the  Treponema  paUidum  in  mouth  lesions  as  frequently  as 
other  workers. 

How,  then,  are  we  going  to  diagnose  syphilis  in  mouth  lesions, 
where  the  Spirochccta  dcntium  occurs  normally?  First,  as  all  are 
agreed,  the  surface  layer  should  be  rubbed  off  with  a  cotton  or 
gauze-covered  probe,  wet  in  distilled  water.  Then  the  part  should 
be  still  further  curetted,  if  necessary,  until  a  drop  of  pure  serum 
appears.  If  this  serum  is  examined,  the  Spirochccta  dentium  is 
not  likely  to  be  found.  If  then,  a  spirochseta  is  demonstrated 
that  is  over  10  microns  in  length,  we  may  be  reasonably  sure  that 
we  are  dealing  with  the  organism  of  syphilis.  Bu  the  step  to 
emphasize  is  the  obtaining  of  serum  without  surface  contamina- 
tion. In  genital  lesions,  so  far  as  I  know,  the  Spirochccta  dentium 
has  not  been  found ;  and  coarse  forms  are  not  at  all  likely  to  be 
mistaken  for  the  delicate  Treponema  pallidum. 

Summary. 

The  nigrosin  method  of  demonstrating  spirochaetje  and  trypa- 
nosomes  gives  a  much  smoother  background  than  India  ink. 

A  thinner  film  can  be  made  than  with  India  ink,  therefore 
minute  details  are  better  seen.  Some  bacterial  flagella  are  readily 
demonstrated. 


282  DANDRIDGE   MEMORIAL 

This  article  also  discusses  the  morphologic  distinctions  between 
the  Spirochcsta  dentium  and  the  Treponema  pallidwn,  with  the 
following  conclusions : 

In  many  mouth  lesions  the  Spirochceta  dentium  has  been  mis- 
taken for  the  Treponema  pallidum.  To  prevent  such  a  mistake 
it  is  important  to  remove  the  surface  layer  of  a  lesion,  and  ex- 
amine the  clear  serum  obtained  from  the  deeper  parts.  If,  then, 
an  organism  is  found  longer  than  10  microns,  with  deep  windings, 
it  is  reasonably  certain  to  be  the  Treponema  pallidum. 

In  conclusion,  I  wish  to  express  my  thanks  to  Professor  Wool- 
ley  for  the  syphilitic  material,  and  to  Professor  Wherry  for  the 
trypanosome  material,  as  well  as  for  many  helpful  suggestions. 

REFERENCES. 

1  Hecht  and  Wilenko :  Wien.  klin.  Wochenschr.,  1909,  xxii,  932. 

2  Barach:  Journal  A.  M.  A.,  1910,  Iv,  1892. 

3  Gins :  Centralbl.  f.  Bacteriol.,  1909,  Hi,  620. 

4  Gins:  Centralbl.  f.  Bacteriol.,  1911,  Ivii,  472. 

5  Certes :  Bull.  Soc.  Zool.  de  France,  1888,  xiii,  230.  Reference  taken 
from  Lee's  Microtomist's  Vade  Mecum,  Ed.  vi,  484. 

6  Fabre-Domergue :  Ann.  de  Micr.,  1889,  ii,  545.  Jour.  Roy.  Micr.  Soc, 
1889,  832. 

7  Park  and  Williams :  Pathogenic  Bacteria  and  Protozoa,  New  York, 
Ed.  iv,  573. 

8  Hoffmann :  Aetiologie  der  Syphilis,  Berlin,  1906.  Referred  to  by 
Gerber  (see  note  12). 

9  Plaut :  Demonstration  von  Spirochseten  mit  dem  Burrischen  Tusch- 
evervahren.  Miinchen.  med.  Wchnschr.,  1910.  Reference  from  Gerber 
(see  note  12). 

10  Levaditi  et  Mcintosh :  Contribution  a  I'etude  de  la  culture  de  Trepo- 
nema pallidum.  Ann.  de  I'lnst.  Pasteur,  1907,  xxi.  Reference  from  Ger- 
ber (see  note  12). 

11  Gurd:  Journal  A.  M.  A.,  1910,  liv,  1779. 

12  Gerber:  Centralbl.  f.  Bacteriol.,  1910,  Ivi,  508. 

13  Zweig:  Farbung  der  Spirochasta  pallida  in  vivo  nach  Meirowski. 
Med.  Klin.,  1910,  vi,  21. 


ON  THE  CONTRACTION  OF  CATGUT  AND  THE 
THEORY  OF  MUSCULAR  CONTRACTION.* 


WILLIAM    II.   STRIETMANN,    M.D.^   AND   MARTIN    11.   FISCHER,    M.D. 


The  problem  of  muscular  contraction  naturally  divides  itself  into 
three  parts — a  study  of  the  physical  changes  that  characterize  the 
muscular  contraction,  a  study  of  the  chemical  changes  that  under- 
lie this  phenomenon,  and  lastly,  that  which  is  usually  regarded  as 
the  most  important  part  of  the  whole,  the  means  by  which  the 
chemical  energy  regarded  as  the  source  of  the  muscular  contraction 
is  converted  into  the  mechanical.  The  physical  changes  of  mus- 
cular contraction  have  by  all  odds  received  the  greatest  amount 
of  study ;  next  in  order  stand  the  chemical  changes.  Least  agree- 
ment exists  at  the  present  time  in  the  matter  of  how  the  chemical 
changes  lead  to  the  mechanical.  It  is  more  particularly  toward 
the  solution  of  this  phase  of  the  problem  that  these  paragraphs 
are  intended  to  contribute.  What  we  have  to  say  is  best  begun  by 
detailing  the  results  of  a  few  experiments  on  the  contraction  of 
catgut. 

I.    OBSERVATIONS    ON    THE   CONTRACTION    OF   CATGUT. 

1.  As  is  well  known  since  the  classical  studies  of  T.  W.  Engel- 
mann,^  it  is  possible  to  make  raw  catgut  undergo  alternately  a 
marked  shortening  and  an  elongation  by  changing  the  character  of 
the  surroundings  in  which  the  catgut  is  placed.  Engelmann  found 
that  catgut  suspended  in  water  shortened  greatly  when  the  water 
was  heated,  to  lengthen  once  more  when  this  was  subsequently 
cooled.  The  following  experiments  show  how  such  alternate  con- 
tractions and  relaxations  may  be  brought  about  by  other  changes 
in  the  surroundings  of  the  catgut. 

2.  We  prepared  the  catgut  used  in  our  studies  from  the  com- 
mercial raw  catgut  sold  to  surgeons,  or  from  violin  strings,  the 
material  employed  by  Engelmann.  The  catgut  strings  were  soaked 

*  Reprinted  from  Kolloid  Zcitschrift,  10,  65,  1912. 

283 


284 


DANDRIDGE   MEMORIAL 


in  distilled  water  before  being  used,  after  which  they  were  split 
into  as  thin  strands  as  possible.  One  such  strand  may  be  used  for 
an  experiment,  but,  in  order  to  get  greater  contractile  force,  it  is 
best  to  use  several  as  is  shown  in  Fig.  1,  a.  Here  four  strands  of 
catgut  of  uniform  diameter  have  been  fastened  to  the  glass  rod. 


Fig-.  1  a. 


Fig  1  b. 


It  is  best  to  wrap  the  glass  rod  with  silk  thread  in  order  to  keep 
the  strands  from  slipping.  The  four  strands  are  then  gathered 
together  at  the  bottom  with  a  silk  thread  and  the  whole  is  fitted 
into  a  muscle  lever  such  as  physiologists  use,  arranged  to  write  on 
a  recording  drum.  The  whole  is  set  up  in  such  a  way  as  to  make 
it  possible  to  bathe  the  catgut  strands  with  any  desired  solution 
without  in  any  way  disturbing  the  apparatus  as  indicated  in  Fig. 


STRIETAIANN     AND     FISCHER  285 

3.  When  a  single  strand  of  catgut,  or  a  set  arranged  as  already 
described,  has  been  permitted  to  absorb  as  much  water  as  it  will 
by  being  kept  in  distilled  water  (or  in  a  "physiological"  salt  solu- 
tion") no  change  occurs  in  the  catgut,  as  evidenced  by  any  move- 
ment of  the  lever,  over  long  periods  of  time.  The  point  of 
the  lever  writes  a  straight  line.  If  we  remove  the  beaker  holding 
the  distilled  water  and  substitute  for  it  another  containing  a  dilute 
acid  of  some  kind  (lactic  or  hydrochloric  is  best)  it  is  noticed 
that  after  a  slight  latent  period  the  strands  begin  to  contract  and 
the  lever  point  writes  a  curve  as  shown  in  Fig.  2,  I.  After  ob- 
taining a  maximal  amount  of  shortening,  a  horizontal  line  is 
written  as  long  as  the  catgut  remains  in  the  acid  solution.  If  this 
is  now  taken  away  (indicated  by  the  right  hand  arrow  in  Fig.  2) 


Fig.  2. 

and  the  distilled  water  is  replaced,  the  lever  point  begins  to  fall, 
and  slowly  returns  to  its  old  base-line  level. 

The  height  of  the  contraction  is  dependent  in  a  very  interesting 
way  upon  the  strength  of  the  acid  solution.  Curve  I  of  Fig.  2 
was  obtained  by  passing  from  distilled  water  to  a  1-40  normal 
hydrochloric  acid  solution  and  then  back  to  distilled  water.  Curve 
II  was  obtained  in  an  identical  way  with  a  1-60  normal  hydro- 
chloric acid,  and  Curve  III  with  a  1-80  normal  acid.  This  indi- 
cates that  the  greater  the  concentration  of  the  acid,  the  higher  the 
contraction.  To  this  there  is,  however,  an  upper  limit.  A  1-40 
normal  hydrochloric  acid  represents  very  nearly  the  optimal  one 
for  the  contraction  of  catgut  strands.  Curve  IV,  which  is  the 
lowest  of  the  series  in  Fig.  2,  was  obtained  with  a  1-20  normal 
hydrochloric  acid. 

4.  The  state  of  the  catgut  is  of  importance  in  determining  the 
height  of  the  contraction.  Freshly  soaked  catgut  gives  tlie  high- 
est contractions.  If  the  catgut  is  allowed  to  remain  in  the  distilled 
water  for  several  days,  the  height  of  the  contraction  as  obtained 
with  any  given  concentration  of  acid  becomes  progressively  less. 


286  DAN  BRIDGE   MEMORIAL 

This  is  shown  in  Fig.  3,  where  are  recorded  the  contraction  curves 
obtained  with  the  same  strands  of  catgut  used  to  produce  Fig,  2, 
after  they  had  been  kept  in  water  for  five  days.  As  the  recording 
lever,  the  weight  carried,  etc.,  were  the  same  in  both  series  of  ex- 
periments, the  two  sets  of  curves  may  be  compared  with  each 
other  directly.  Curves  I,  II  and  III  in  Fig.  3  were  obtained  with 
the  same  concentrations  of  hydrochloric  acid  as  those  similarly 
marked  in  Fig.  2.  What  is  the  nature  of  the  changes  in  the  catgut 
induced  by  prolonged  immersion  in  distilled  water  we  are  not 
prepared  to  say,  although  we  are  most  inclined  to  think  them  due 
to  the  digestion  of  the  protein  material,  catalyzed  in  part  no  doubt 
by  the  ferments  derived  from  the  bacteria  which  get  into  the 
vessels  holding  the  catgut  in  our  ordinary  laboratory  experiments. 
5.  Fig.  4  shows  the  effect  of  the  thickness  of  the  catgut  strand 


Minuien 

Fig.  3. 

upon  the  contraction.  In  this  experiment  only  single  strands  of 
the  same  length  could  of  course  be  used.  The  concentration  of 
acid  employed  was  1-40  normal  hydrochloric  in  each  case;  c  in- 
dicates the  curve  obtained  with  the  thickest  fiber,  a  that  with  the 
thinnest.  It  is  readily  apparent  that  the  contraction  results  the 
more  rapidly  the  thinner  the  fiber.  Curve  a  is  not  as  high  as  the 
other  two.  As  the  weight  lifted  was  the  same  with  all  three  fibers, 
such  a  result  is  easily  accounted  for  on  the  basis  of  the  relatively 
higher  stretching  force  applied  to  the  fiber  in  the  case  of  a  than  in 
the  case  of  the  other  two. 

6.  We  noted  above  that  the  catgut  strands  relax  entirely  when 
the  acid  solution  in  which  they  have  contracted  is  replaced  by  dis- 
tilled water.  To  get  a  complete  relaxation,  however,  takes  a  very 
long  time.  In  other  words,  the  fiber  maintains  a  residuum  of  con- 
traction. What  this  amounts  to,  after  repeated  transitions  of  the 
catgut  from  water  to  acid  and  then  back  to  water,  is  indicated  in 
Fig.  5.  On  the  first  passing  from  water  (base  line)  into  1-40  nor- 
mal hydrochloric  acid  we  obtain  the  maximal  contraction  indicated 
by  the  first  rise  of  the  line.    This  is  a  record  taken  on  a  still  drum. 


STRIETMANN    AND    FISCHER         287 

The  first  horizontal  plateau  records  the  maximal  contraction,  made 
by  rotating  the  drum  slightly  forward.  The  fall  in  the  record  ob- 
tained on  changing  to  water  fails  to  reach  the  original  base  line. 
On  again  passing  to  acid  the  second  rise  is  obtained,  and  it  will  be 
noted  that  this  is  higher  than  the  original  contraction.  The  sec- 
ond fall  on  immersion  in  water  does  not  even  reach  the  low  point 


T 


Hinufen 


Fis.  4. 


previously  attained,  and  so  on  for  a  series  as  indicated  in  the 
figure.  Then  for  a  long  period  the  contractions  and  relaxations 
remain  equal,  and  there  are  no  appreciable  changes  in  the  levels 
of  the  maximal  and  minimal  points  attained.  But  if  the  series  of 
changes  from  acid  into  water  and  back  again  were  kept  up  long 
enough,  it  is  clear  that  the  maximal  points  attained  must  become 
progressively  lower,  and  that  the  amount  of  residual  contraction 
must  diminish,  due  to  changes  suffered  by  the  catgut  (digestion  ?). 
The  justification  for  such  a  conclusion  is  found  in  the  dift'erences 


Fig.  5. 


observable  in  the  curves  of  contraction  obtained  from  fresh  and 
old  catgut  (Figs.  2  and  3). 

7.  In  Fig.  6  is  shown  the  eft'ect  of  various  amounts  of  a  neu- 
tral salt  upon  the  contraction  of  catgut  in  an  acid  solution.  Curve 
I  shows  the  contraction  of  a  series  of  strands  when  immersed  in 
a  1-50  normal  hydrochloric  acid.  The  moment  of  immersion  is 
indicated  by  the  arrow  a.  At  c  the  acid  is  replaced  by  water  and 
relaxation  results.  Curve  II  was  obtained  by  immersing  the  cat- 
gut at  the  point  a  not  in  a  pure  acid  but  in  one  containing  in  addi- 


I II  i 


M 

E 


bo 


S3   ^  l=< 


STRIETMANN    AND     FISCHER  289 

tion  0.25  per  cent,  sodium  chloride  solution,  at  the  point  b  in  a  pure 
0.25  per  cent,  sodium  chloride  solution,  the  relaxation  occurring 
as  indicated.  Curves  III,  IV,  V  and  VI  were  obtained  in  identical 
fashion  by  alternate  immersion  of  the  catgut  in  1-40  normal  hydro- 
chloric acid  containing  respectively  0.5,  0.75,  1.0  and  3.0  per  cent, 
sodium  chloride,  and  then  in  0.5,  0.75,  1.0  and  3.0  per  cent,  pure 
sodium  chloride.  In  Curve  VI  it  will  be  noted  that  the  power  of 
the  acid  in  bringing  about  a  contraction  has  been  suppressed  en- 
tirely. As  a  matter  of  fact  the  fibers  have  contracted  even  less 
than  in  pure  water  (the  curve  lies  slightly  below  the  base  line). 

8.  The  series  of  curves  in  Fig.  7  show  an  extremely  interesting 
contrast  to  those  of  Fig.  6.  Curve  I  is  again  a  contraction  fol- 
lowed by  a  relaxation  as  obtained  by  alternate  immersion  of  the 
catgut  in  a  1-50  normal  hydrochloric  acid  solution  and  in  pure 
water.  Curves  II,  III,  IV,  V  and  \'I  were  obtained  by  immer- 
sion in  acid  of  the  same  concentration,  but  the  solutions  con- 
tained in  addition  respectively  0.25,  0.5,  0.75,  1.0  and  5.0  per  cent, 
sodium  chloride.  At  points  lying  between  the  arrows  b  and  c, 
these  solutions  were  replaced  by  pure  ivater.  In  every  case  fur- 
ther contraction  is  obtained  before  the  relaxation  sets  in,  which 
occurred  immediately  in  Fig.  6  when  we  passed  to  salt  solutions 
instead  of  pure  water. 

Results  identical  with  those  portrayed  in  Figs.  6  and  7  are 
obtained  if  any  other  rcid  (such  as  lactic)  is  used  in  place  of 
the  hydrochloric  acid,  or  any  other  salt  (such  as  sodium  lactate) 
takes  the  place  of  the  sodium  chloride.  Neither  is  it  necessary 
that  the  salt  and  the  acid  used  shall  have  a  common  ion.  Any 
salts  will  depress  the  contractions  obtainable  in  any  acid. 

In  Fig.  8  the  facts  already  noted  in  Fig.  7  are  brought  out  in 
a  slightly  different  way.  In  the  first  portion  of  the  curve  is  noted 
the  contraction  obtained  in  a  pure  acid  solution.  Between  the 
two  points  marked  Ringer  solution  the  catgut  strands  were  im- 
mersed in  this  solution  after  which  water  was  substituted  for  it. 
As  is  readily  apparent,  one  obtains  under  such  circumstances 
a  second  contraction  which  is  practically  as  high  as  that  obtained 
initially. 

10.  In  Fig.  9  is  shown  the  effect  of  immersion  of  catgut 
strands  in  successivelv  greater  concentrations  of  the  same  acid. 


290  DAN  BRIDGE   MEMORIAL 

As  we  pass  from  one  to  the  other  we  get  a  greater  and  greater 
contraction  until  the  maximal  contraction  is  obtained  in  the  high- 
est (optimal)  concentration  of  the  acid. 

11,  Thus  far  the  relaxations  of  the  catgut  after  immersion  in 
an  acid  have  been  obtained  by  using  either  water  or  a  neutral 
salt.  The  relaxation  occurs  much  more  rapidly  and  the  base  line 
is  regained  sooner  if  for  the  neutral  salt  is  substituted  one  that 
has  the  power  of  combining  wnth  the  acid  used  to  induce  the 
contraction.  The  effect  of  this  is  shown  in  Fig.  10.  In  this  case 
the  contraction  was  obtained  in  a  one-half  normal  hydrochloric 
acid,  the  relaxation  in  a  one-fifth  molecular  sodium  bicarbonate 
solution. 

II.      INTERPRETATION    OF  EXPERIMENTAL  FINDINGS. 

It  requires  no  imagination  to  see  in  Fig.  10  a  duplicate  of  the 
tracing  obtained  when  ordinary  striated  muscle  is  made  to  con- 
tract. But  before  we  discuss  this  further  let  us  see  with  what 
general  phenomena  in  colloid  chemistry  we  may  correlate  the 
above  described  experimental  results.- 

Catgut  chemically  considered  is  a  protein,  and  its  general 
physico-chemical  reactions  betray  its  colloid  character.  The  fact 
that  it  swells  in  water  at  once  serves  to  class  it  with  the  lyophili>'. 
or  emulsion  colloids,  or,  as  water  is  the  absorbed  substance,  with 
the  hydrophilic  colloids.  On  a  merely  superficial  examination, 
therefore,  catgut  seems  to  belong  in  a  group  with  gelatin,  fibrin 
or  serum  albumin.  But  it  behaves  like  these  protein  colloids  in 
various  other  directions  also.  When  we  observe  that  on  immer- 
sion in  a  dilute  acid  the  catgut  fiber  contracts,  we  note  at  the 
same  time  that  it  does  this  by  a  process  of  swelling;  it  becomes 
thicker  and  shorter.  The  same  thing  is  noted  in  tnc  case  of  gela- 
tin, fibrin  or  serum  albumin.  Gelatin  or  fibrin  swells  more  in  any 
dilute  acid  than  in  pure  water,  and  the  viscosity  of  serum  albu- 
min rises  when  acid  is  added  to  it.  If  the  acid  is  washed  out  of 
these  colloids,  they  resume  their  original  form  once  more,  as  does 
the  catgut  when  water  replaces  the  acid  solution.  Just  as  gelatin 
and  fibrin  show  within  certain  limits  an  increase  in  the  amount 
of  swelling  with  every  increase  in  the  concentration  of  the  acid 
surrounding  them,  so  also  do  we  note  an  increased  height  of 


STRIETMANN    AND     FISCHER  291 

contraction  in  catgut  when  the  acid  concentration  surrounding 
this  increases. 

The  fact  that  catgut  does  not  at  once  return  to  a  previous 
state  when  the  conditions  about  it  are  changed  has  its  analogue  in 
the  way  in  which  fibrin,  gelatin,  etc.,  only  slowly  recover  from 
the  effects  of  a  previous  surrounding,  when  a  new  one  is  substi- 
tuted for  it  (hysteresis). 

With  a  given  concentration  of  acid,  the  amount  of  svv'elling 
attained  by  gelatin,  fibrin  or  serum  albumin  is  reduced  by  the 
presence  of  any  salt  (even  neutral  salts,  and  such  having  no  ion 
in  common  with  the  acid),  and  this  reduction  in  the  swelling  is 
the  greater,  the  stronger  the  concentration  of  the  added  salt. 
The  parallel  of  this  is  found  in  the  reduction  of  the  height  of 
the  contraction  of  catgut  in  any  acid  solution,  when  any  salt  is 
added,  the  reduction  being  the  greater  the  higher  the  concentra- 


Xo"  HCI  ^Rin^er-sdie 


flinuten 

Fig.  8 

tion  of  the  added  salt.  When  fibrin  has  been  allowed  to  swell 
to  its  maximum  in  a  mixture  of  any  acid  with  a  salt,  and  is  then 
placed  in  pure  water,  an  initial  increased  swelling  of  the  fibrin 
is  noted,  before  the  decrease  sets  in  which  brings  the  fibrin  back 
to  the  degree  of  swelling  characteristic  of  immersion  in  pure 
water.  It  is  as  though  the  acid  were  united  more  firmly  to  the 
protein  colloid  than  are  the  salts.  In  spite  of  greater  diffusion 
velocity  of  acids  over  salts,  the  salts  nevertheless  seem  to  get  out 
of  colloidal  proteins  more  rapidly  than  do  the  acids,  an  observa- 
tion not  without  biological  importance,  nor  without  interest  for 
the  theory  of  the  colloidal  state.  This  behavior  or  fibnu  also 
has  its  analogue  in  the  already  observed  characteristics  in  the 
contraction  of  catgut  when  changed  from  a  salt-acid  mixture  to 
pure  water. 

Point  for  point,  therefore,  the  contraction  and  relaxation  of 
catgut  (absorption  and  secretion  of  water  by  catgut)  is  identical 
with  the  taking  up  and  giving  off  of  the  water  by  various  oth^. 
colloidal  proteins. 


292  DAXDRIDGE   MEMORIAL 

It  is  easily  seen  at  the  same  time  how  these  experiments  on 
cal.yut  contractions  correlate  themselves  with  the  experiments  of 
Engelmann.  What  happens  is  identical  in  both  instances,  namely, 
an  absorption  and  secretion  of  water  by  the  proteins  composing 
the  catgut,  only  while  Engelmann  used  an  increase  in  tempera- 
ture to  make  the  catgut  swell,  we  used,  for  purposes  that  will  be- 
come evident  immediately,  various  acids. 

III.       ON    THE    ANALOGY    BETWEEJST    THE    DESCRIBED    CONTRACTION 
OF    CATGUT,   AND    THE    CONTRACTION    OF    STRIATED    MUSCLE. 

It  is  easily  seen  how  similar  are  many  of  the  curves  illustrat- 
ing this  paper  with  the  curves  obtained  and  familiar  to  every 
physiologist  wdien  striated  muscle  contracts. 

Fig.  10  could  easily  be  mistaken  for  the  record  of  an  ordinary 
nuscle  twutch.     In  Fig.  9  we  observe  a  series  of  successively 


Xzonici        ^     ;go"iiCl      <     Zo^nCi    "■  ;<o''l1Cl 


fihinuren 


Fig.  9 


higher  contractions  that  remind  us  of  the  result  obtained  when 
a  series  of  inadequate  stimuli  are  thrown  at  proper  intervals  into 
a  striated  muscle.  Fig.  8  illustrates  a  phenomenon  of  rigor  in 
catgut  that  Edward  B.  Meigs  has  described  in  muscle.  If  a  frog's 
muscle  is  immersed  in  a  weak  acid  it  goes  into  a  state  of  contin- 
ued contraction ;  if  it  is  now  placed  in  Ringer  solution  it  relaxes 
to  contract  a  second  time  if  it  is  subsequently  placed  in  water. 

The  series  of  curves  shown  in  Fig.  6  (and  the  first  half  of 
the  curves  of  Fig.  7)  illustrate  in  catgut  what  we  call  fatigue  in 
striated  muscle.  The  last  half  of  the  curves  of  Fig.  7  show  again 
the  contractions  obtained  in  moving  from  an  acid  solution  contain- 
ing salt  into  pure  water  as  already  referred  to  in  Fig.  8.  Fig.  5 
illustrates  the  staircase  phenomenon  familiar  to  us  from  muscle 
physiology.  Not  only  are  the  successive  contractions  of  the  cat- 
gut fiber  progressively  higher,  but  the  fiber  does  not  relax  per- 
fectly ;  there  remains  the  residual  contraction  or  increased  tone 
of  our  muscle  preparations.     Fig.  4  shows  how  a  catgut  fibril 


STRIETMANX    AND     FISCHER  293 

may  remain  continuously  contracted  (tetanus).  When  we  com- 
pare Figs.  2  and  3,  and  note  how  the  same  catgut  fiber  undergoes 
changes  in  its  state  which  alter  markedly  its  power  to  contract 
under  given  conditions,  we  recognize  the  analogue  of  the  import- 
ance of  the  state  of  the  muscle  in  our  physiological  experiments 
as  determining  the  character  of  its  contraction. 

The  question  now  arises  whether  these  physical  analogies 
between  the  contraction  curves  written  by  muscle,  and  those  writ- 
ten by  the  catgut  strings  as  described  above  constitute  merely  a 
happy  coincidence,  or  whether  the  two  processes  are  really  in 
essence  the  same;  in  other  words,  is  the  contraction  of  striated 
muscle  a  simple  problem  in  colloid  chemistry  just  as  we  found 
the  contraction  of  catgut  to  he?  This  is  our  belief.  The  aniso- 
tropic substances  of  the  muscle  corresponds  to  the  catgut  threads ; 


Minuten 

^'■.T.  10. 

the  isotropic  substance  or  sarcoplasm  to  the  water  that  surrounds 
the  catgut  threads. 

But  does  our  analog}^  between  the  contraction  process  in  cat- 
gut and  in  muscle  extend  beyond  these  physical  likenesses ;  in 
other  words,  are  the  chemical  surroundings  that  we  used  to  make 
catgut  contract  identical  with  those  that  make  striated  muscle 
contract?  This,  we  think,  is  also  the  case.  In  fact,  we  sur- 
rounded our  catgut  w'ith  the  very  chemical  conditions  which  our 
present  day  physiology  holds  to  exist  in  muscle  in  the  various 
phases  of  its  contraction. 

That  a  muscle  produces  acid  during  an  ordinary  contraction 
constitutes  one  of  the  classic  facts  of  our  physiolog>'.  This  state- 
ment has  only  recently  been  generalized  to  the  extent  of  saying 
that  whenever  a  muscle  is  found  to  contract  evidence  of  acid 
production  in  the  muscle  exists.    The  contraction  of  rigor  mortis 


294  DANDRIDGE  MEMORIAL 

is  associated  with  the  production  of  acid  in  the  muscle,  a  fact 
which  made  L.  Hermann,  in  calHng  attention  to  the  analogies  that 
exist  between  the  contraction  of  muscle  in  rigor  mortis  and  the 
ordinary  muscle  contraction,  venture  the  suggestion  that  the  or- 
dinary single  muscle  twitch  was  due  to  a  temporary  production 
of  acid  in  the  muscle.  More  recently,  particularly  through  the 
work  of  Fletcher,  Hopkins  and  Meigs,  it  has  been  shown  that  in 
water  rigor,  heat  rigor,  chloroform  rigor,  etc.,  the  contractions 
noted  under  these  circumstances  are  also  always  associated  with 
the  production  of  acid  in  the  muscle. 

But  not  only  is  the  production  of  acid  associated  with  every 
contraction  of  muscle,  but  it  is  the  cause  of  this,  as  has  been 
shown  particularly  well  by  McDougall  and  Meigs.  McDougall 
studied  the  effects  of  acids  and  various  other  conditions  on  the 
length  of  the  isolated  contractile  elements  of  insect  wing  muscle. 
He  found  these  to  shorten  whenever  he  brought  them  in  contact 
with  any  very  dilute  acid.  With  increasing  concentration  of  the 
acid  he  found  that  an  optimum  was  reached,  beyond  which  a 
lessened  contraction  vv^as  observable.  It  will  be  recalled  that  we 
described  this  same  phenomenon  in  catgut.  When  the  muscle 
elements  were  removed  from  the  acid  solution  to  pure  water,  re- 
laxation set  in.  The  relaxation  occurred  more  rapidly  if  instead 
of  being  placed  in  distilled  water  the  muscle  elements  were  placed 
in  a  sodium  chloride  solution.  The  more  highly  concentrated 
this  was  the  more  rapidly  did  the  relaxation  set  in. 

Meigs  has  greatly  amplified  these  experimental  observations 
and  described  practically  identical  findings  in  frog's  muscle. 

From  these  few  remarks  it  is  clear  that  the  chemical  condi- 
tions which  we  described  above  as  effective  in  producing  and 
modifying  the  contraction  of  catgut  are  identical  with  those  which 
do  the  same  in  striated  muscle,  wherefore  we  conclude  that  the 
phenomenon  of  contraction  in  mnscle  is  entirely  a  problem  in 
colloid  chemistry.  If  this  conclusion  is  justified,  then  let  us 
briefly  review  some  of  our  current  theories  of  muscular  contrac- 
tion with  an  eye  to  discovering  which  of  them  are  most  nearly 
correct.  In  so  doing  we  will  find  that  the  proponents  of  these 
theories  have  erred  not  so  much  through  a  failure  to  recognize 
that  muscular  contraction  represented  a  colloidal  problem,  but 


STRIETMAXX    AND    FISCHER         295 

rather  in  that  they  did  not  consider  this  explanation  adequate  or 
capable  of  accounting  for  more  than  a  small  part  of  the  essential 
phenomena  of  contraction. 

IV.      HISTORICAL  AND  CRITICAL  REMARKS. 

For  the  first  great  step  toward  the  formulation  of  a  colloidal 
theory  of  contraction  we  are  indebted  to  Franz  Fiofmeister,^ 
that  old  master  who  has  done  so  much  to  establish  the  biological 
importance  of  the  colloidal  state  Hofmeister  built  upon  the 
fact  that  protoplasm  consists  of  a  series  of  bodies  that  are  cap- 
able of  imbibing  water,  and  pointed  out  how  in  the  processes  un- 
derlying the  phenomena  of  imbibition  a  migration  of  water  and 
the  approximation  of  two  points  (contraction)  that  are  sur- 
rounded by  envelopes  of  water  must  occur  whenever  the  imbibi- 
tion capacity  of  the  one  is  increased  at  the  cost  of  the  other.  In 
this  way  he  tried  to  account  for  all  the  special  types  of  protoplas- 
mic contraction  as  observed  in  different  animal  and  plant  forms. 

The  missing  element  in  Hofmeister's  theor}- — which  he  him- 
self points  out — is  that  he  could  not  explain  why  the  colloids 
suffered  the  changes  which  make  for  the  contraction;  in  other 
words,  the  nature  of  the  chemical  changes  that  induced  the  phy- 
sical. For  a  first  proposition  in  this  direction  we  are  indebted 
to  T.  W.  Engelmann.* 

Engelmann  started  from  the  w^ell-known  fact  that  during 
muscular  contraction  the  carbohydrates  and  fats  disappear  from 
the  muscle,  and  that  carbon  dioxide,  water,  etc.,  appear  in  their 
place.  This  chemical  change  is  associated  with  the  liberation  of 
heat,  and  this  fact  Engelmann  utilized  to  construct  upon  it  his 
thermodynamic  theory  of  muscular  contraction.  Briefly  formu- 
lated, Engelmann  believes  that  the  muscular  contraction  is  initi- 
ated by  a  chemical  change  in  the  carbohydrates  (and  fats)  of  the 
muscle  which  results  in  the  liberation  of  heat;  this  heat  acting 
upon  the  contractile  elements  contained  in  the  muscle  (the  aniso- 
tropic substance)  makes  them  absorb  the  isotropic  substance 
and  so  swell  and  shorten.  The  physical  half  of  this  theory,  it 
will  be  noted,  is  also  an  inhibition  theory  of  the  nature  of  Hof- 
meister's. To  support  his  contention,  Engelmann  devised  his  now 
famous  catgut  experiment,  in  which  he  showed  how  this  catgut — 


296  DANDRIDGE   AIEMORIAL 

which  is  also  anisotropic — contracts  in  water  when  its  temperature 
is  raised,  to  relax  again  when  the  temperature  falls.  If  the  cat- 
gut strand  is  only  momentarily  heated,  a  contraction  curve  is  ob- 
tained which  is  identical  in  appearance  with  a  single  muscle 
twitch. 

Engelmann's  theory  has  been  attacked  on  many  sides,  to  our 
minds  often  with  scant  justice  when  the  substituted  theories  are 
weighed  in  the  balance  against  his.  The  best  argument  against 
it  are  furnished  by  two  facts.  First,  the  amount  of  heat  produced 
during  an  ordinar}^  muscular  contraction  is  not  sufficient  to  make 
anisotropic  substance,  of  the  nature  of  that  found  in  muscle, 
shorten  enough  to  explain  a  muscular  contraction.  Second,  a 
contraction  of  muscle  occurs  under  circumstances  in  which  there 
may  be  no  production  of  heat  whatsoever.  But  even  after  all  this 
is  granted,  the  great  fact  remains  that  Engelmann  was  the  first 
to  create  a  satisfactory  model  of  the  muscular  contraction  out 
of  materials  which  may  be  subjected  to  physico-chemical  analysis, 
and  so  to  remove  the  \/hole  problem  from  a  realm  of  speculation 
and  terminology  into  one  of  reason  and  fact.  As  will  be  evident 
later,  even  in  the  matter  of  making  a  change  in  temperature  re- 
sponsible for  the  physical  phenomena  of  contraction,  he  was  not 
entirely  wrong;  he  only  failed  to  pick  the  most  powerful  explo- 
sive out  of  a  series  lying  before  him. 

The  work  of  L.  Hermann  furnishes  a  valuable  contribution  to 
the  establishment  of  a  colloidal  theory  of  muscle  contraction  in 
several  directions.  Hermann  emphasized  very  clearly  the  many 
analogies  both  from  a  chemical  and  physical  standpoint  that  exist 
between  the  ordinaiy  muscular  contraction  and  the  various  rigors. 
As  "coagulation"  is  an  obvious  sign  in  the  rigors,  the  question  of 
whether  the  ordinary  muscular  contraction  is  a  "temporary  coagu- 
lation, or  a  kind  of  coagulation,"  has  often  been  argued  since 
Hermann's  writings.  Hermann  took  the  signs  of  coagulation  and 
the  contraction  of  muscle  in  rigor  to  represent  evidences  of  one 
and  the  same  process,  and  believed  both  of  them  to  be  due  to 
the  formation  of  acid  in  the  muscle  which  occurs  in  all  the  rigors. 
In  such  a  belief  he  was  in  part  right,  in  part  wrong.  In  making 
the  production  of  acid  responsible  for  both  he  was  right,  but  to 
understand  properly  what  happened  beyond  this  point  was  im- 


STRIETMANN    AND    FISCHER  297 

possible  then,  for  colloid  chemistry  had  not  as  yet  developed  suffi- 
ciently. 

We  know  now  that  the  obvious  signs  of  any  "coagulation" 
such  as  that  which  characterizes  the  rigors  to-day  can  only  be 
associated  with  a  loss  of  water  by  the  "coagulated"  colloid.^  As 
the  muscular  contraction  consists  of  an  absorption  of  water,  just 
the  reverse  of  "coagulation,"  it  is  clear  that  the  "coagulation" 
and  the  contraction  observed  in  muscle  in  rigor  must  be  entirely 
separate  processes.  What  happens  in  muscle  is  identical  with  the 
development  of  a  clouding  in  the  cornea  of  an  eye  simultaneously 
with  the  swelling  of  the  enucleated  eye  when  this  is  placed  in  acid- 
ulated water,*'  or  the  development  of  a  "cloudy  swelling"  in  any 
of  the  parenchymatous  organs  when  these  are  exposed  to  the  same 
condition/  Two  colloids  at  least  are  involved  in  the  process,  and 
luhile  the  one  is  behaving  like  gelatine  zvhich  szcells  in  acidulated 
water,  the  other  behaves  like  casein  which  under  the  same  circum- 
stances is  precipitated.  In  rigor  the  anisotropic  substance  szcells 
under  the  influence  of  the  acid  and  leads  to  the  muscular  con- 
traction, while  under  the  same  circumstances  another  colloid  is 
being  precipitated  {or,  to  use  Herinann's  word,  "coagulated")  and 
giz'es  the  muscle  an  opaque  appearance.  As  we  shall  see  later, 
the  loss  of  water  by  the  one  colloid  which  is  being  "coagulated" 
no  doubt  yields  that  necessary  for  the  swelling  (contraction)  of 
the  other. 

Whether  a  rigor  is  reversible  or  not  depends  entirely  upon 
whether  the  precipitation  of  the  colloid  involved  is  reversible  or 
not ;  whether,  in  other  words,  removal  of  the  condition  which  has 
made  the  colloid  precipitate  permits  this  to  go  back  into  solution. 
Depending  upon  the  means  employed  to  produce  the  rigor  and 
the  length  of  time  it  has  acted,  the  colloidal  precipitations  may  or 
may  not  be  reversible,  and  so  the  rigor. 

This  matter  of  rigor  can,  in  a  sense,  also  be  mimicked  on  cat- 
gut.  If  we  allow  a  chromium  salt  to  act  upon  the  catgut  along 
with  any  acid,  then  we  get  not  only  a  shortening  of  the  catgut,  but 
a  permanent  one. 

In  applying  the  observation  that  the  acid  production  in  rigor  is 
responsible  for  the  permanent  contraction  here  as  in  the  ordinary 
muscular  contraction,  Hermann^  made  the  further  valuable  sug- 


298  DANDRIDGE  MEMORIAL 

gesticn  that  a  temporary  production  of  acid  in  muscles  might  ac- 
count for  the  norm.al  muscular  contraction.  But  this  remained  a 
mere  suggestion  with  Hermann. 

The  idea  that  the  production  of  acid  is  responsible  for  the 
muscular  contraction  either  under  normal  circumstances  or  in 
rigor  has  been  particularly  clearly  enunciated  by  William  Mc- 
Dougall.^  This  author  holds  the  anisotropic  substance  (the  sar- 
comeres or  contractile  elements  of  the  muscle)  to  be  built  up  of 
tubules  "having  delicate  walls  and  containing  a  fluid  or  viscid  sub- 
stance." The  contraction  he  holds  to  be  due  to  an  absorption  of 
fluid  by  these  tubules  "determined  by  the  setting  free  of  lactic  acid 
in  the  fluid  contents  of  the  sarcomere,  aided  perhaps  by  an  in- 
crease in  the  osmotic  equivalent  of  these  fluid  contents  through  an 
increase  in  the  number  of  molecules  in  solution.  Then  so  long  as 
the  acid  remains  present  in  the  fluid  of  the  sarcomere,  the  addi- 
tional fluid  absorbed  will  be  retained  and  the  state  of  contraction 
will  continue.  But  as  soon  as  the  acid  escapes  from  the  sarcomere 
the  additional  fluid  will  also  escape  with  it  into  the  sarcoplasm 
and  allow  relaxation  to  take  place." 

With  McDougall's  description  of  the  histology  of  striated 
muscle  we  are  not  immediately  concerned;  in  passing  we  would 
only  point  out  that  much  of  the  discussion  as  to  whether  a  histo- 
logical structure  is  "solid"  or  "liquid"  is  purposeless,  for  animal 
and  plant  structures  are  chiefly  colloidal  in  composition,  and  the 
colloids  that  compose  living  matter  combine  in  one  the  prop- 
erties usually  cited  as  characteristic  of  both  the  solid  (mainte- 
nance of  form)  and  the  liquid  state  (surface,  tension,  dift'usion 
of  dissolved  substances). 

It  is  clear  that  ^^JcDougall's  ideas  readily  permit  one  to  see 
why  a  single  muscle  twitch,  a  tetanus,  or  a  rigor  due  to  death, 
acid  or  water,  all  have  the  phenomenon  of  contraction  in  common, 
underlying  all  of  them  is  the  production  of  acid  in  the  muscle; 
and  depending  upon  whether  this  acid  production  is  only  temp- 
orary or  permanent  we  have  either  a  temporary  or  a  continued 
state  of  contraction. 

IMcDougall  worked  with  isolated  muscle  fibrils.  If  these  are 
placed  in  a  weak  solution  of  any  acid  (acetic  or  lactic)  they  swell 
and  shorten.     If  now  they  are  placed  in  distilled  water  and  the 


ST  R  I  EM  AX  N    AXD    FISCHER  299 

acid  is  washed  out  of  them  they  relax  again.  When  the  acid  ex- 
ceeds a  certain  optimal  concentration  the  shortening  becomes  less 
marked.  If  any  salt  is  present  in  the  dilute  solution  of  the  acid, 
the  contraction  is  lessened,  or  may  not  appear  at  all.  If  fibrils 
that  have  undergone  no  marked  contraction  in  a  solution  contain- 
ing both  acid  and  salt  are  transferred  to  pure  water,  they  undergo 
a  rapid  shortening.  We  need  not  do  more  than  merely  indicate 
the  fact  that  these  statements  are  point  for  point  identical  with 
those  we  made  above  regarding  the  contraction  and  relaxation  of 
catgut  under  similar  circumstances. 

The  theoretical  views  of  AIcDougall  have  found  excellent  ex- 
perimental support  and  have  won  precision  through  the  careful 
studies  of  Edward  B.  Aleigs.^''  This  author  has  not  only  collected 
the  evidence  which  shows  that  an  acid  production  underlies  every 
phenomenon  of  contraction  as  observed  in  striated  muscle,  but 
he  was  the  first  to  recognize  and  clearly  express  the  fact  that  we 
deal  in  this  problem  (in  part  only,  according  to  Meigs)  with  a 
colloidal  phenomenon,  and  that  the  acid  owes  its  action  to  the 
fact  that  it  makes  certain  colloids  of  the  muscles  swell. 

Since  Meigs'  writings  McDougalP^  has  also  expressed  this 
idea  in  unequivocal  terms. 

W'ith  this  colloidal  view  of  the  muscular  contraction  we  heart- 
ily concur.  The  criticisms  we  have  to  make  of  ]\IcDougall  and 
Meigs'  ideas  are  that  on  both  theoretical  and  experimental  grounds 
they  do  not  consider  the  colloidal  conception  entirely  adequate. 
McDougall  believes  that  in  the  process  of  contraction  osmotic 
effects  play  a  part  in  addition  to  the  colloidal,  while  Meigs 
thinks,  in  his  analysis  of  the  problem  of  water  absorption  by  the 
muscle,  that  osmotic  phenomena  are  concerned  here.  No  experi- 
ments are  cited  to  support  ]\IcDougairs  osmotic  hypothesis,  and 
as  Meigs,  who  is  the  best  champion  of  McDougall's  ideas,  agrees 
that  the  swelling  of  the  contractile  elements  in  muscle  (the  es- 
sence of  contraction)  is  a  colloidal  phenomenon,  we  may  con- 
sider it  settled  that  at  least  so  far  osmotic  phenomena  do  not 
play  a  role. 

In  holding  to  the  view  that  the  "living"  muscle  is  surrounded 
by  osmotic  membranes,  Meigs  supports  his  position  by  calling 
attention  to  the  curve  of  water  absorption    exhibited  by  a  muscle 


300  DANDRIDGE  MEMORIAL 

immersed  in  distilled  water.  Such  a  muscle  rapidly  attains  a 
maximal  swelling,  then  for  a  period  loses  in  weight,  gains  in 
weight  a  second  time,  and  then  slowly  loses  again. ^-  The  curve 
representing  the  second  gain  in  weight  comes  at  the  same  time 
and  accompanies  the  contraction  of  the  striated  muscle,  and  this 
Meigs  is  willing  to  accept  as  a  process  of  colloidal  swelling 
(swelling  of  the  contractile  elements  under  the  influence  of  an 
acid).  But  the  first  swelHng  Meigs  does  not  consider  as  of  the 
same  type.  He  here  follows  the  older  belief  of  E.  Overton,  that 
osmotic  membranes  exist  about  the  "living"'  muscle  cell.  When 
excised  and  placed  in  distilled  water,  these  osmotic  membranes 
are  destroyed,  in  part  owing  to  the  accumulation  of  acid  within 
the  muscle,in  part  due  to  differences  in  osmotic  concentration  in- 
side and  outside  of  the  muscle  cell  which  lead  to  their  rupture. 
When  the  membranes  are  thus  destroyed,  the  fluid  behind  them 
is  allowed  to  escape,  and  so  the  muscle  loses  temporarily  in 
weight.  But  this  temporary  loss  in  weight  can  be  interpreted 
more  simply  as  a  phenomenon  in  colloid  chemistry.  The  muscle 
contains  several  colloids,  and  the  maximal  swelling  and  precipita- 
tion points  for  any  given  set  of  conditions  are  not  the  same  for 
all  these  colloids.  Under  the  influence  of  an  acid,  for  example, 
the  maximal  swelling  of  the  one  may  therefore  be  attained  and 
exceeded  sooner  than  that  of  another,  and  so  a  swelling  of  one 
colloid  in  the  muscle  may  have  reached  and  gone  beyond  its  maxi- 
mum (an  increase  followed  by  a  decrease  in  weight)  before  an- 
other has  attained  its  maximum.  As  a  matter  of  fact  we  know 
that  just  such  a  relationship  must  exist  between  the  different  col- 
loids in  a  striated  muscle  when  this  contracts  normally.  There  is 
no  free  water  in  the  body ;  it  is  all  held  in  combination  with  the 
colloids  of  the  tissues."  If  one  colloidal  element  in  an  organism 
swells  (say  the  anisotropic  substance),  it  can  do  this  only  as  it 
first  robs  some  other  element  of  its  content  of  water.  It  would 
be  eminently  useful,  therefore,  if  the  conditions  which  on  the 
one  hand  make  for  a  swelling  of  the  anisotropic  substance,  make 
on  the  other  for  the  shrinkage  (giving  up  of  water)  of  another 
(isotropic  substance). 

To  our  mind  all  that  characterizes  the  phenomena  of  water 
absorption  and  contraction  in  muscle,  together  with  the  various 


STRIEMANN    AND    FISCHER  301 

phenomena  of  '"coagulation"  observed  in  the  rigors,  repres^ent  but 
simple  expressions  of  the  effect  of  various  acids  and  salts  on 
that  mixture  of  the  several  protein  colloids  which  make  up  the 
muscle.  We  propose  shortly  to  deal  further  with  this  subject. 
Here  we  would  only  direct  attention  once  more  to  Fig.  8  and  the 
apparently  complicated  series  of  reactions  that  may  be  obtained 
from  a  simple  catgut  fibril  when  exposed  to  the  action  of  water, 
acids  and  salts.  It  is  reactions  of  this  type  in  muscle  that  have 
given  rise  to  the  highly  complicated  beliefs  regarding  the  exist- 
ence of  membranes,  etc.,  about  the  individual  muscle  cells.  As 
a  matter  of  fact,  we  have  no  more  reason  for  postulating  their 
existence  here  than  in  the  case  of  our  catgut. 

]\Iuch  of  the  confusion  that  exists  to-day  in  this  whole  prob- 
lem of  contraction,  water  absorption,  irritability,  etc.,  as  observed 
in  muscle,  arises  from  the  fact  that  various  authors  have  too 
carelessly  passed  from  observations  made  on  one  to  conclusions 
regarding  another,  instead  of  studying  each  phenomenon  sepa- 
rately. Association  of  phenomena  does  not  make  them  identical. 
As  we  have  learned  that  the  signs  of  coagulation  observed  in  rigor 
mortis  are  not  identical  with  the  phenomena  of  contraction  in  the 
same  condition,  so  also  does  water  absorption  not  parallel  loss  of 
irritability,  or  loss  of  irritability  mean  a  loss  of  the  power  of 
contraction. 

SUMMARY. 

This  paper  attempts  to  contribute  to  the  establishment  of  a 
colloid-chemical  theory  of  contraction  in  striated  muscle.  A 
series  of  experiments  on  the  swelling  and  contraction  of  catgut 
is  described,  and  it  is  pointed  out  how  these  phenomena  are  not 
only  identical  with  the  physical  phenomena  of  contraction  as 
observed  in  striated  muscle,  but  how  the  chemical  conditions  de- 
termining both  are  also  identical.  A  review  is  given  of  the  work 
of  those  men  who  have  contributed  most  to  the  establishment  of 
a  colloid-chemical  theory  of  contraction,  and  to  this  are  appended 
some  critical  remarks. 

REFERENCES. 

1  T.  W.  Engelmann:  Pfliiger's  Archiv,  7,  loo  (1873);  Uebcr  den  Ur- 
sprung  der  Muskelkraft.    Leipzig,  1893. 

2  K.  Spiro,  Wolfgang  Ostwald,  Martin  H.  Fischer,  and  Wolfgang 
Pauli. 


302  DAN  BRIDGE  MEMORIAL 

3  F.  Hofmeister :  Die  Lehre  von  der  Pflanzenzelle.  Leipzig,  1867.  Not 
accessible  in  the  original. 

4  T.  W.  Engelmann:  Pfliiger's  Archiv,  7,  155  (1873)  ;  Ueber  den  Ur- 
sprung  der  Muskelkraft.     Leipzig,  1893. 

5  See  Wolfgang  Pauli :  Kolloid  Zeitschr.,  7,  241  (1910)  ;  Pauli  and  H. 
Handovsky:  Biochem.  Zeitschr.,  18,  340  (1909)  ;  24,  239  (1910)  :  H.  Han- 
dovsky:  Kolloid  Zeitschr.,  7,  183.  267  (1910)  ;  Fortschritte  in  der  Kolloid- 
chemie  der  Eiweisskorper,  Dresden,  1911;  Karl  Schorr:  cited  by  Pauli  and 
Handovsky. 

6  Martin  H.  Fischer:  Pfliiger's  Archiv,  127,  40  (1909). 

7  Martin  H.  Fischer:  Kolloid  Zeitschr.,  8,  159  (1911). 

8  L.  Hermann:  Hermann's  Handbuch  der  Physiologic,  1,  255  (1879). 

9  William  McDougall :  Journal  of  Anatomy  and  Physiology,  32,  187 
(1898). 

10  E.  B.  Meigs:  Zeitschr.  f.  allg.  Physiol.,  8,  81  (1908):  Am.  Jour. 
Physiol.,  22,  477  (1908);  Ibid.,  26,  191  (1910);  Jour.  Physiol.,  39,  385 
(1909). 

11  McDougall:  Quarterly  Jour.  Exp.  Physiol.,  3,  S3  (1910). 

12  Martin  H.  Fischer:  Pfliiger's  Archiv,  124,  69  (1908);  E.  B.  Meigs: 
American  Journal  of  Physiology,  26.  191  (1910). 

13  Martin  H.  Fischer:  Das  Oedem,  192,  Dresden,  1910;  KoUoidchem- 
13  Martin    H.    Fischer:    Oedea,    192,    New    York,    1910;    Kolloidchem- 

ische  Beihefte,  2,  304  (1911). 


AN  ANO^IALOUS  DUCT  BELONGING  TO  THE 
URINARY  TRACT.* 


BY  PAUL  G.  WOOLLEY,   M.D.,  AND  HERBERT  A.  BROWX,  M.D. 


The  specimen  we  wish  to  describe  is  of  unusual  interest  because 
of  its  extreme  rarity,  for,  in  spite  of  a  somewhat  painstaking 
search  of  the  Hterature  we  have  found  no  account  of  any  similar 
condition.  It  was  found  during  the  post-mortem  on  a  patient  in 
the  Cincinnati  Hospital  (No.  153426)  who  had  been  admitted  for 
cutaneous  blastomycosis,  and  who  died  of  the  generalized  form  of 
that  disease. 

Because  none  of  the  symptoms  of  the  patient  could  be  referred 
in  any  way  to  the  condition  of  the  genito-urinary  tract  we  shall 
omit  the  history  and  report  of  the  autopsy,  and  confine  ourselves 
to  an  account  of  the  condition  only  as  it  referred  to  the  specimens. 
We  believe  that  this  case  has  been  discussed  from  the  dermato 
logical  standpoint  by  Dr.  Ravogli. 

The  left  kidney  weighed  200  gms.  The  capsule  stripped  witlr 
slight  difficulty  and  left  a  moderately  roughened,  almost  nodula 
surface.  The  cut  section  was  rather  pale,  and  the  line  of  de- 
markation  between  cortex  and  m.edulla  v.'as  indistinct.  The 
cortex  was  of  about  normal  thickness.  The  blood  vessels  were 
sclerotic.  The  right  kidney  showed  the  same  general  appearance. 
The  left  adrenal  showed  a  somewhat  evident  hyperplasia  of  th'" 
medulla.     The  right  adrenal  was  apparently  absent. 

Extending  from  the  antero-mesial  aspect  of  the  upper  pole  of 
the  right  kidney,  that  is,  from  the  normal  site  of  the  right  adrenal, 
appeared  a  distended,  tortuous,  saculated  tube,  wdiich  ran  paralle\ 
with  the  right  ureter  which  it  finally  passed  to  enter  the  posterior 
surface  of  the  prostate  gland.  The  average  diameter  of  this 
sac  was  about  2  cm.  In  its  wider  parts  it  was  distended  to  about 
4-5  cm.     At  its  lower  end  it  was  rapidly  constricted,  almost  to 

*  Reprinted    from   The  Johns  Hopkins  Hospital  Bulletin,  Vol.  XXII, 
No.  244,  July,  1911. 

303 


304  DAN  DRIDGE  MEMORIAL 

the  immediate  vicinity  of  the  prostatic  part  was  a  blastomycotic 
abscess  which  involved,  to  a  minimal  extent,  the  wall  of  the  duct. 
The  upper  part  of  this  distended  duct  ended  in  a  mass  of  tissue 
of  about  2x1x1  cm.  in  size,  which  was  taken  to  be  the  remains 
of  an  atrophic  adrenal  and  which  later  proved  to  contain  only  one 
small  area  which  in  any  way  resembled  adrenal  tissue.  This  mass 
also  contained  abscesses.  There  was  no  connection  whatever  be- 
tween the  tube  and  the  kidney,  ureter  or  bladder.  The  pelvis  of 
the  kidney  was  not  dilated.  Both  testicles  were  present  and  had 
undergone  descensus. 

In  the  expectation  that  sections  of  the  specimen  would  be  of 
some  assistance,  bits  of  tissue  were  taken  from  the  nodule  of 
tissue  at  the  renal  extremit}^,  from  the  sac  at  its  origin  near  this 
renal  nodule  and  from  the  prostatic  portion  of  the  tube.  The 
blocks  of  tissue  taken  from  the  uppermost  part  included  the 
nodule  itself  and  the  kidney  so  that  comparison  could  be  made  in 
the  same  section. 

The  sections  made  from  these  blocks  can,  for  the  purposes  of 
description,  be  divided  into  three  parts ;  one,  representing  the 
mass  of  the  nodule ;  a  second  representing  the  kidney ;  and  a 
third,  the  boundary  zone  betv/een  nodule  and  kidney. 

The  tissue  of  the  first  part  was  for  the  most  part  well-formed 
fibrous  tissue  enclosing  large  and  small  cystic  spaces,  large  and 
small  blood  vessels,  nerves,  collections  of  epithelial  cells  (colum- 
nar, as  a  rule,  occasionally  cubical),  which  seem  to  represent  cross 
sections  of  ducts,  and  the  blastomycotic  abscesses.  The 
larger  cystic  spaces  were  lined  with  a  single  row  of  cuboidal  epi- 
thelium and  filled  with  a  granular  albuminous  material  in  which 
masses  of  desquamated  epithelium,  polymorphonuclear  leucocytes, 
giant  cells,  and  blastomyces,  were  imbedded.  The  smaller  cystic 
spaces  were  of  two  particular  forms.  One  form  was  lined  with 
one  or  more  rows  of  cylindrical  or  high  columnar  epithelium  and 
filled  with  desquamated  cells,  cellular  detritus,  leucocytes,  and 
extra-  and  intra-cellular  blastomyces ;  the  other  vvas  lined  with 
one  or  more  layers — usually  a  single  layer — of  cuboidal  epithelium 
and  contained  a  material  that  greatly  resembled  thyroid  colloid. 
Occasionally  this  colloid  showed  concentric  lines  and  in  some 
cases  it  was  so  changed  that  it  stained  with  basic  dyes  and  ap- 


Fk;.   1. 

Ii.Lu.STRATioxs. — 1.  ii  pliotojjrapli  of  tlie  jrross  specimen:  2.  the  atl renal  (?)  rest:  i.  same 
as  2.  enlarged:  4.  cystic  spaces  showing  colloid:  5.  cystic  space  showing  corpus  amylaceuni: 
6.  ducts  in  the  nodule  above  the  kidney:  7.  wall  of  the  larsj-e  duct. 

All  of  the  illustrations  except  1  and  .i  were  drawn  with  a  c;iniera  liicida  at  table  lieiy:ht 
usinsi  a  I.citz  ocular  IV  anil  obj.  .?.  Fitrure  .^  was  drawn  with  a  I.eitz  ocular  IV  and  a  Spen- 
cer -I  mm.  A  ii.Sii  olijeotive. 


V     't      ji.  .<•        *,  S    '••■'■u'     J,'  'l-    t**V 


Fk..   4. 


;vx^^/^ 


Fig.  6. 


Fig. 


WOOLLEY    AND    BROWN  305 

pearcd  quite  similar  in  appearance  to  the  corpora  amylacea  of  the 
prostate  gland.  As  a  rule,  however,  they  were  rather  more 
irregular  than  the  ordinary  prostatic  corpora  amylacea,  and  had 
a  striking  resemblance  to  other  similar  bodies  that  are  occasionally 
present  in  the  ovary  and  other  organs.  The  blood  vessels  had,  as 
a  rule,  thickened  walls  and  in  the  majority  of  instances  showed 
endothelial  proliferation,  even,  in  some  cases,  to  the  point  of  ob- 
literation. The  nerves  showed  no  abnormalities,  either  in  cross 
or  longitudinal  sections.     No  ganglion  cells  were  observed. 

The  tissue  of  the  second  part  represented  merely  a  narrow 
zone  of  kidney  tissue  in  which  there  were  general  changes  that 
taken  collectively  indicated  a  chronic  diffuse  nephritis  of  mod- 
erate severity. 

The  boundary  zone  between  the  two  parts  already  described 
was  composed  of  f  brous  tissue  that  firmly  united  the  kidney  and 
the  nodule.  This  zone  was  of  some  little  width,  but  the  line  of 
demarcation  was  narrow,  and  was  represented  by  a  narrow  line 
of  renal  capsule.  In  but  a  few  sections,  close  to  the  kidney,  and 
yet  separated  distinctly  from  it  were  small  localized  masses  of 
tissue,  glandular  in  structure,  and  quite  similar  to  the  tissue  that 
is  seen  in  adrenal  and  renal  adenomas,  and  in  which  was  no  sign 
of  ganglion  or  chromaffin  cells. 

The  general  impression  given  by  these  sections  was  that  one 
was  dealing  with  a  possible  combination  of  renal,  adrenal,  and 
ovarian  tissue  indifferently  arranged.  Drs.  Knower  and  Wieman 
have  suggested  the  occasional  resemblance  to  a  Wolffian  body. 

The  sections  from  the  sac  itself  at  the  upper  and  lower  ends 
>show  that  the  walls  of  the  sac  were  composed  of  fibrous  tissue 
with  a  minimal  number  of  smooth  muscle  fibers  and  were  lined 
with  low  columnar  or  cuboidal  epithelium. 

There  are,  under  more  or  less  normal  circumstances,  possi- 
bilities of  but  three  openings  into  the  prostatic  urethra — two,  the 
openings  of  the  ejaculatory  ducts,  which  were  present  in  this  case, 
and  one,  the  opening  of  the  united  Miillerian  ducts. 

There  is  also  the  theoretic  possibility  that  as  a  result  of  em- 
bryonic developmental  variations  as  suggested  by  Pohlman  the 
ureter  might  open  into  the  prostatic  urethra.  Pohlman  says  that 
in  changing  its  position  on  the  A\''olffian  duct  from  dorsal  to  lat- 


306  D  A  NDR  I  DGE  MEMORIAL 

eral,  at  which  time  the  ureter  comes  to  open  distinct  from  the 
Wolffian  duct  and  would  naturally  open  in  common  with  it  or  into 
parts  developed  from  its  lower  end,  or  "the  ureter  might  open 
laterally  to  the  Wolffian  duct  and  on  a  level  with  it.  The  opening 
in  this  case  would  be  found  in  the  prostatic  urethra." 

If  this  be  a  true  explanation,  then  the  mass  of  tissue  above  the 
kidney  is  the  remnant  of  an  atrophic  or  h^-poplastic  kidney,  or  it 
is  the  remains  of  the  Wolffian  body.  In  the  former  case  we 
should  be  dealing  with  a  unilateral  multiplicity  of  kidneys,  each 
with  its  ureter,  one  of  which  opens  into  the  prostate ;  in  the  latter 
we  should  have  to  consider  that  the  duct  was  the  result  of  per- 
sistence of  the  united  Wolffian  duct  and  ureter. 

There  is  the  other  possibility  that  in  this  case  we  are  merely 
idealing  with  an  abnormal  course  of  a  complete  ureter  without  any 
participation  of  a  Wolffian  duct,  as  occasionally  happens  in  cases 
with  accessory  ureters.  It  is  to  be  noted  that  in  such  cases 
one  of  the  ureters,  usually  the  one  which  has  the  superior  origin, 
lies  deeper  and  may  open  into  the  colliculus  seminalis,  the  vas 
'deferens  or  the  seminal  vesicle.  In  any  case  we  cannot  account 
for  absence  of  the  adrenal  except  on  the  basis  of  aplasia,  or  per- 
haps— if  the  nodule  mentioned  above  be  adrenal — hyperplasia. 
Either  of  these  results,  it  might  be  suggested,  may  be  the  result  of 
the  development  oi'  accessory  renal  tissue  at  the  expense  of  ad- 
renal. The  embryonic  relationships  of  the  urogenital  organs  are 
so  close  that  the  possibilities  of  variations  are  very  numerous. 
Marchand  emphasized  this  from  the  side  of  the  genito-adrenal 
organs  when  he  suggested  that  variations  in  the  sizes  of  adrenals 
and  ovaries  cannot  be  considered  as  purely  fortuitous. 

It  is  our  misfortune  that  the  anatomic  evidence  at  our  disposal 
is  not  sufficient  to  permit  us  to  come  to  any  decision  as  to  whether 
?we  are  dealing  with  the  result  of  one  or  the  other  of  the  possi- 
bilities mentioned. 

LITERATURE. 

Pohlman :  Amer.  Med.,  1904,  987. 

Marchand:  Intern.  Beitraege  z.  Wissensch.  Med.,  Virchow's  Festschrift, 
Bd.  1. 

Aschoff:  Pathologische  Anatomie,  Jena,  1909,  Bd.  11,  S.  506. 
Kaufmann :  Specielle  Pathologische  Anatomie,  Berlin,  1907,  S.  IIZ. 


THE  GER^IICIDAL  ACTIOX  OF  BASIC  FUCHSIN.* 


EUGENE   S.    MAY,   M.D. 


"Fucpisix  (rubin  is  obtained  by  the  oxidation  of  a  mixture 
of  aniline,  ortho-  and  paratoluidin,  by  means  of  arsenious  acid 
or  nitrobenzol  in  the  presence  of  iron  chloride,  which  acts  as  the 
means  of  carrying  over  the  acid.  It  is  soluble  in  water,  alcohol 
and  aniyl  alcohol.  Rubin  is  'basic  dye-stuff'  and  serves  for  the 
staining  of  cell  nuclei,  fuchsinophile  granulations  and  bacteria."^ 
A  convenient  classification  of  the  aniline  dyes,  that  of  Krieger,- 
places  the  three  salts  of  fuchsin  in  the  rosaniline  group.  The 
members  of  this  group  are : 

Methyl  violet,     6  B.  C^,  H30  N.,  CI. 
^lalachite  green,    C23  H25  No  CI. 
Rosaniline  acetate,     Qo  H20  ^'3  CL  H3  O.. 
Rosaniline  hydrocliloride,    C20  Hgo  N3  CI. 
Rosaniline  sulphate,     (C20H20N32)  SO4. 

It  is  only  with  the  last  three  members  of  this  group,  rosaniline 
acetate,  hydrochloride  and  sulphate,  that  Ave  shall  be  concerned. 
These  three  salts  are  generally  known  as  the  fuchsins.  The 
acetate  is  the  most  basic,  and  the  sulphate  most  acid  in  reaction, 
and  it  is  the  acetate  which  is  furnished  us  as  basic  fuchsin,  and 
the  hydrochloride  and  sulphate  as  acid,  or  ordinary  fuchsin.  This 
difference  of  chemical  reaction  in  these  salts  is  of  importance, 
since  Krieger-  has  shown  that  the  greater  the  degree  of  basicity 
of  the  dye  the  greater  is  its  germicidal  action.  Our  experiments 
confirm  these  findings,  with  the  exception,  that  our  results,  when 
testing  the  germicidal  action  of  the  acid  salts  upon  bacteria,  have 
been  uniformly  negative. 

METHODS. 

There  are  many  technical  difficulties  in  the  handling  of  the 
problem  and  many  observers  have  attempted  to  work  out  a  tech- 
nique which  will  not  be  open  to  criticism.  Ainley  Walker  and 
:^Iurry2  added  such  dye-stuffs  as  Grubler's  methyl  violet,  fuchsin 

307 


308  DAN  BRIDGE  MEMORIAL 

and  methylene  blue,  in  (0.2  per  cent.)  solution,  to  culture  media 
(principally  plain  agar-agar),  sterilizing  the  media  in  the  ordinary 
way.  They  often  noted  the  precipitation  out  of  the  coloring 
matters  to  the  bottom  of  the  tubes.  They  then  inoculated  the 
tubes  with  the  bacterium  under  investigation  and  their  experi- 
ments prove  that  very  interesting  morphological  and  biological 
changes  occur  in  bacteria  which  are  grown  upon  culture  media  so 
prepared.  They  found  that  the  motility  of  the  bacillus  typhosus 
was  lost,  that  the  bacillus  was  replaced  by  a  thread-like  organism, 
twenty  to  thirty  times  as  long  as  the  original  bacillus.  No  seg- 
mentation was  noted,  though  branching  forms  were  frequently 
encountered.  With  the  work  of  Walker  and  Murry  as  a  basis 
many  observers  accepted  the  fact  as  proven  that  the  bacillus  were 
dead.  This  we  believe  to  be  an  error,  since  the  tubes  were  not 
under  observation  for  a  sufficient  length  of  time.  We  have  noted 
growth  in  tubes  after  seven  or  eight  days,  where  no  growth  had 
been  observed  after  forty-eight  and  seventy-two  hour^.  This 
phenomenon  is  readily  explained  by  an  inhibitory  rather  than  a 
germicidal  action  of  the  dye  (as  proven  by  Geppert,  quoted  by 
Krieger). 

Further,  we  have  noted  a  very  great  difference  in  the  germi- 
cidal action  of  the  dye,  according  to  whether  the  inoculations  have 
been  made  into  warm  or  cold  solutions ;  cold  solutions  being  for 
the  most  part  non-germicidal,  while  warm  solutions  are  uniformly 
active.  Again,  we  have  noted  many  times  that  solutions  from 
which  all  pigment  has  been  precipitated,  by  careless  sterilization, 
had  completely  lost  their  power  to  kill  bacteria.  Because  of  heat 
applied  during  the  sterilization  of  solutions  of  the  dye  chemical 
changes  occur  in  the  dyestufT  itself,  perhaps  new  and  entirely 
different  chemical  compounds  are  produced  and  these  are  appar- 
ently more  active  than  the  original  dyestuff  itself. 

Koch  used  what  is  known  as  the  silk  thread  method.  He 
placed  sterile  silk  threads  in  emulsions  of  bacteria,  and  then  al- 
lowed them  to  dry  for  twenty-four  hours.  They  were  then  intro- 
duced into  sterile  solutions  of  various  dyes  and  tested  out. 

Krieger  dismisses  the  technique  of  Koch  as  open  to  error  and 
bases  his  technique  upon  the  work  of  Walker  and  Murry.  Briefly, 
Krieger's^  own  method  of  investigation  is  this :    Bacterial  sus- 


M  A  Y  309 

pensions  were  prepared  from  cultures  and  emulsified  in  sterile 
physiological  salt  solution,  then  filtered,  and  drops  of  the  filtrate 
carried  over  with  platinum  loops  to  the  sterile  cover  slips ;  the 
cover  slips  were  then  placed  in  the  incubator  for  one  hour  (till 
dry)  ;  then  the  cover  slips  were  transferred  to  the  various  dye 
solutions  for  variable  periods  of  time,  washed  in  water,  and  after- 
wards dropped  into  broth  tubes.  If  no  growth  resulted  (length 
of  time  of  observation  not  stated),  it  was  taken  for  granted  that 
the  micro-organism  was  dead.  Many  sources  of  error  arose,  as 
he  himself  notes ;  too  long  drying  may  weaken  or  kill  the  bacteria, 
or  they  may  be  mechanically  washed  off. 

Our  own  technique  is  about  as  follows  and  we  believe  that  we 
have  obviated  nearly  all  source  of  error : 

Carefully  weighed  quantities  of  basic  fuchsin  (Grubler's)  was 
made  up  into  a  stock  solution  of  1.00  per  cent,  with  double  dis- 
tilled water  and  placed  in  sterile  bottles  and  kept  away  from  the 
action  of  light.  From  this  stock  1.00  per  cent,  solution  higher 
dilutions  were  made,  as  0.75  per  cent.,  0.5  per  cent.,  0.25  per  cent., 
0.1  per  cent.,  0.075  per  cent.,  0.025  per  cent.,  0.01  per  cent.,  and 
0.001  per  cent. ;  5.00  c.c.  of  these  solutions  were  run  into  thor- 
oughly cleansed,  sterile  test  tubes,  and  then  sterilized  in  flowing 
steam  in  the  Arnold  sterilizer  for  fifteen  minutes  on  three  suc- 
cessive days.  This  we  determined  after  many  trials  to  be  about 
the  limit  of  sterilization.  Greater  heat  or  more  prolonged  heating 
brought  about  a  precipitation  of  the  dye. 

The  germicidal  action  of  these  stock  fuchsin  solutions  was 
tested  in  the  following  manner:  Three  loops-full  of  the  water  of 
condensation  from  twenty-four  hour  agar  slant  cultures  was  car- 
ried over  to  the  standard  basic  fuchsin  solution  and  thoroughly 
mixed.  The  bacteria-fuchsin  solution  thus  prepared  was  then 
constantly  kept  at  a  temperature  of  about  40°  during  the  whole 
of  the  experiment.  Immediately,  and  at  intervals  of  one,  five, 
fifteen,  thirty,  forty  and  sixty  minutes,  three  loop-fulls  of  the 
w^arm  bacteria-fuchsin  mixture  was  inoculated  upon  a  culture 
medium  known  to  be  favorable  for  the  growth  of  the  micro-or- 
ganism under  investigation.  Controls  were  made  and  the  tubes 
incubated  at  37°  for  from  seven  to  fourteen  days.  Careful  note 
was  made  of  the  presence  of  growth  from  day  to  day,  in  order  to 


310  DANDRIDGE  MEMORIAL 

ascertain  that  the  resuUs  were  not  due  to  an  inhibitive  action  of 
the  dye  upon  the  bacteria.  In  several  instances  the  original 
bacteria-fuchsin  solution  was  also  incubated  with  the  other  tubes, 
and,  at  the  end  of  two  weeks,  centrifugalized  and  the  bacteria 
thoroughh-  washed  with  sterile  physiological  salt  solution  and 
new  sub-cultures  made.  In  all  instances  no  growth  was  noted. 
Also  the  dye  was  first  added  to  the  culture  media  and  then  the 
inoculations  were  made.  These  served  as  controls  for  any  in- 
hibitory action  of  the  dye.  As  a  routine  all  bacteria-fuchsin  mix- 
tures were  incubated,  and  at  the  end  of  fourteen  days  sub-cultures 
were  made  with  negative  results. 

The  germicidal  action  of  the  fuchsin  solutions  was  tested  upon 
B.  coll,  B.  typhosus,  B.  paratyphosus,  B.  enterifidis  (Gaertner), 
B.  dyscntericc,  staphylococcus  pyogenes  aureus,  a  saprophytic 
strain  of  B.  tuberculosis,  Oidiuni  albicans  from  the  human  throat 
and  Oidia  from  a  case  of  generalized  blastomycosis.  The  culture 
of  B.  coli  was  isolated  from  a  case  of  chronic  cystitis  with  per- 
sistent colonuria.  It  was  with  a  view  of  combating  this  latter 
condition  that  this  research  was  originally  undertaken.  All  of 
these  stock  cultures  were  furnished  me  by  Dr.  W.  B.  Wherry,  to 
whom  I  am  much  indebted  for  advice  and  assistance. 

The  following  table  summarizes  our  bacteriological  investiga- 
tions. In  this  table  results  as  given  are  constant.  We  have  shown 
repeatedly  that  fuchsin  is  germicidal  in  much  higher  dilutions 
than  here  shown  (1-10000  to  1-100000),  and  it  should  be  remem- 
bered that  the  action  of  these  higher  dilutions  is  variable. 

It  will  be  noted  that  a  warm  0.1. per  cent.  (1-1000)  solution 
was  lethal  in  five  minutes  to  B.  coli,  B.  typhosus,  B.  paratyphosus, 
B.  enteritidis,  B.  dysentericc,  and  the  staphylococcus  pyogenes 
aureus,  while  the  blaslomxyces  was  not  killed  in  less  than  fifteen 
minutes.  In  the  case  of  B.  tuberculosis  and  Oidium  albicans  lethal 
action  was  not  manifested  by  higher  dilutions  than  warm  1.0  per 
cent.  (1-100)  solution  acting  for  five  minutes. 

We  have  made  several  animal  experiments  to  show  the  non- 
toxicity  of  the  dye.  With  warm  1  per  cent,  solutions  we  have 
made  repeated  irrigations  of  the  urinary  bladders  of  rabbits. 
Repeated  and  careful  examination  of  the  urine  and  sections  of  the 
bladders  showed  no  irritation  or  inflammatory  changes.     Basic 


MAY 


111 


Micro-organisms 


*B.  typhosus 
B.  paratyphosus 
B.  coli  com. 
B.  enteritides 
B.  dysenteriss 


tB.  tuberculosis 


♦Staphylococcus 


Time 
of  con- 


Over 


Strength  of       tact  neces-    Warm  Cold    sterilized  Con- 


solution 

1-1000  or  0.1 
per  ct. 

Less  than  0.1 
per  ct.  or 
1-1000 

1-100  or  1 
per  ci. 

Less  than  1 
per  ct.  or 
1-100 


1-1000  orO.l 
per  ct. 

Less  than  0.1 
per  ct.  or 
1-1000 


sary  to  kill     sol.       sol. 
bacteria. 


5-60  min. 


5-60  min. 


5-60  min. 


—     -for: 


sols,      trols 
-fort       -r 


-f  -f-or+  -fort  -f 

-  -fort  +ort  -f 
+  +ort  -fort  -f 

—  -fort  -fort  -f 
-f  -fort  -fort  -f 


fBlastomyces 


tOidium  albicans 


1-1000  or  0.1 
per  ct. 

Less  than  0.1 
per  ct.  or 
1-1000 


1-100  or  1 
per  ct. 

Less  than  1 
per  ct.  or 
1-100 


15-60  min. 


5-60  min. 


—     -1-ort       -fort       4- 


+     -fort       4-ort 


-     -fort       +ort       -f 


+ 


■  or  J 


ort       4- 


-f  =  growth.    —  =  no  growth,    t  =  variable 

*  Subcultures  made  into  -f  1  broth,    t  Subcultures  made  onto 
cose  agar  slants,     (-f  1  =  1  per  cent,  acid  to  phenolphthalein.) 


-1  du- 


fuchsin  has  also  been  injected  into  the  lumbar  subdural  space  of 
dogs  in  1  per  cent,  and  0.1  per  cent,  solutions  with  like  effect.  In 
the  last  two  experiments  the  great  diffnsibility  of  the  dye  is  es- 
pecially well  shown.  This  we  believe  to  be  of  cordial  importance 
in  the  use  of  the  dye  as  a  general  surgical  antiseptic,  since  a  very 


312  D  ANDR  I  DGE  MEMORIAL 

recent  work  of  A.  von  Wassermann,  dealing  with  the  treatment 
of  cancer,  is  based  upon  the  great  diffusibihty  of  a  dye  carrying 
the  therapeutic  agent  to  poorly  vascularized  cancer  cells.  It  is  of 
interest  to  note  that  in  1870  Stilling  advocated  the  use  of  aniline 
dye  solutions  in  surgical  dressings  because  of  its  great  diffusi- 
bility,  harmlessness,  activity,  and  that  it  coagulates  no  albumen. 

CONCLUSIONS. 

1.  Based  upon  the  results  of  our  investigations  with  basic 
fuchsin  we  conclude  that  we  have  a  germicidal  agent  which  is 
more  powerful  than  carbolic  acid  and  one  which  has  a  greater 
diffusibihty  and  is  less  toxic. 

2.  Based  upon  our  clinical  observations  we  conclude  that  we 
have  a  germicidal  agent  which  has  a  marked  stimulative  action 
on  epithelial  and  granulation  tissue  growth. 

We  have  had  as  yet  no  experience  with  the  dye  in  the  treat- 
ment of  lupus  and  blastomycosis.  We  hope  to  soon  be  able  to 
try  basic  fuchsin  out  on  these  cases  and  in  a  later  report  give  the 
results  of  our  investigations. 

REFERENCES. 

1  Rohrman :  Biochemie,  berlin,  1908,  p.  482. 

2  Krieger:  Centralblatt  f.  Bact.,  etc.,  1911,  Bd.  59,  Heft  4,  p.  481. 

3  Walker  (E.  W.  Quinley)  and  Murry:  Brit.  Med.  Jour.,  vol.  11,  p.  16. 

4  Geppert :  Berliner  Klin.  Wochenschr.,  1889,  Nov.  36,  p.  37. 

5  Wassermann,  A.  von:  Deut.  Med.  Woch.,  1911,  No.  24,  p.  531. 

6  Stilling,  J. :  Berl.  Klin.  Wochenschr.,  1870,  No.  24,  p.  531. 


NOTES  OX  TWEXTV-TWO  SPONTANEOUS  TUMORS 
IX  WILD  RATS  (M.  NORVEGICUS).* 


];V  PAUL  G.  WOOLLEV^  M.U.,  AND  \VM.  1!.  WIIERRV,   M.U. 


We  must  express  our  regret  that  the  following  report  does  not 
deal  with  the  inoculability  of  spontaneous  tumors  in  wild  rats. 
This  apparent  lack  of  energy  is  due  to  the  fact  that  the  tumors 
were  found  during  the  systematic  examinations  of  rats  captured 
or  killed  in  San  Francisco  during  the  campaign  for  the  eradication 
of  plague  (1907-08).  The  routine  of  bacteriological  examinations 
left  no  time  for  the  experiments  on  implantation  that  we  should 
have  carried  out  under  other  circumstances. 

In  the  literature  that  we  have  had  at  our  disposal  we  have 
been  able  to  glean  but  little  information  as  to  the  incidence  of 
tumors  in  wild  rats.  The  general  fact  has  been  elicited,  however, 
that  sarcomas  have  been  most  frequently  reported,  and  Opolant 
makes  the  statement  that  whereas  in  mice  95  per  cent,  of  the 
tumors  are  adenocarcinomas  of  mammary  origin,  in  rats  95  per 
cent,  are  sarcomas — a  statement  that  does  not  correspond  with 
Tyzzer's  results  in  the  case  of  mice  nor  with  ^IcCoy's  or  ours  in 
the  case  of  rats.  It  is  true,  however,  that  except  for  McCoy's 
statistics,  few  epithelial  tumors  have  been  reported,  and  this  is  at 
the  bottom  of  the  current  belief  in  the  predominance  of  the  con- 
nective tissue  group  of  tumors.  In  ]\IcCoy's  series  of  ninety-nine 
there  were  forty-eight  epithelial  tumors,  a  percentage  of  48.4  per 
cent.  In  our  series  of  twenty-two  there  were  fourteen  or  63.64  per 
cent.  In  jMcCoy's  series  there  were  thirty  sarcomas  and  eighteen 
libromas ;  a  total  of  forty-eight  tumors  of  fibroblastic  origin. 
The  other  tumors  were  one  lipoma,  one  endothelioma,  and  one 
angioma.  In  our  series  there  were  seven  sarcomas  and  one 
fibroma. 

Our  cases,  like  those  of  ]\IcCoy,  were  all  in  ]\Ius  norvegicus 

*  Reprinted    from    the   Journal   of   Medical  Rcscarcli.  Volume    XXV, 
Xo.  1. 

313 


314  DAXDRIDGE  MEMORIAL 

(decumanus),  a  fact  that  is  undoubtedly  explained  by  the  rela- 
tively small  numbers  of  AIus  rattus  and  Mus  alexandrinus  in  the 
rat  population  of  San  Francisco. 

The  twenty-two  tumors  which  we  report  were  found  in  the 
course  of  the  examination  of  about  twenty-three  thousand  rats, 
and  since  but  one  cf  our  rats  exhibited  more  than  one  growth  it 
is  apparent  that  our  results  compare  well  with  those  of  AlcCoy, 
who  found  that,  on  an  average,  one  rat  in  a  thousand  was  affected 
with  a  tumor  of  one  sort  or  another.  Of  McCoy's  ninety-nine 
reported  cases,  thi  -ty  were  sarcomas,  twelve  carcinomas,  and  one 
endothelioma,  a  total  of  forty-three  malignant  growths.  In  our 
series  were  seven  sarcomas,  one  epithelioma,  one  adenoma,  and 
three  renal  adenomas,  a  total  of  eleven  malignant  growths.  In 
McCoy's  series  sixteen  tumors  showed  metastasis;  in  ours  but 
four.  The  tumors  that  gave  rise  to  metastasis  in  both  series  were 
with  one  exception  (McCoy's  case  of  renal  carcinoma)  sarcomas. 

The  cases  were  as  follows : 

Case  No.  1  (3837).  Adult.  Sex? — A  tumor  about  the  size 
of  a  walnut  was  observed  in  the  right  axilla.  It  was  not  adherent 
to  the  skin  and  was  not  closely  bound  to  the  surrounding  tissues. 
It  was  rather  soft  and  on  section  appeared  whitish  and  had  a 
lobulated  appearance.  It  was  thought  that  it  had  a  definite  re- 
lation to  the  mammary  gland. 

Sections  showed  that  it  \x3.s  a  typical  fibro-adenoma  with  no 
evidence  of  malignancy.  The  sections  showed  a  grossly  lobulated 
appearance.  The  various  lobules  were  composed  of  central  col- 
lections of  parenchymatous  cells  surrounding,  in  a  single  row  or 
occasionally  several  rows,  central  duct-like  spaces  which  were 
filled  with  coagulated  proteid  material.  In  some  instances  the 
coagulated  material  had  an  inspissated  appearance.  Occasionally 
no  lumen  w-as  present  in  the  centers  of  the  parenchymatous  masses 
so  that  the  lobules  were  composed  of  solid  masses  of  cells.  The 
connective  tissue  was  abundant  and  w^ell  formed  and  contained 
considerable  numbers  of  mast  cells. 

Case  No.  2  (5386).  Adult  female. — The  tumor  in  this  case 
was  in  the  left  groin  and  measvired  3.5  x  8.5  centimeters.  Upon 
its  surface  was  an  ulcerated,  punched-out  area  five  millim.eters  in 
diameter.  The  tumor  was  not  adherent,  was  soft,  and  on  section 
white  and  lobulated. 

Sections  showe.l  that  this  tunior  was  similar  to  the  preceding 
(3837),  but  dift'ered  in  that  the  parenchyma  was  somewhat  better 
developed,  and  that  the  connective  tissue  was  more  mature,  and 


WOOLLEY    AND    WHERRY  315 

showed  a  tendency  to  become  hyaline.  The  epithelial  cells  showed 
a  more  constant  increase  in  the  number  of  layers  and  less  coagu- 
lated proteid  in  the  spaces.  There  was  some  tendency  to  inter- 
canalicular  growth.  At  a  single  point  there  was  evidence  of  in- 
vasion of  the  supporting  tissue  by  the  epithelial  cells.  Mitotic 
figures  were  few.    Occasional  direct  divisions  were  observed. 

Case  No.  3  (2).  Adult.  Sex? — A  very  large  tumor  7.5  x  13 
centimeters  in  the  subcutaneous  tissue  of  thorax,  not  adherent, 
white,  lobulated.  It  differed  from  5386  only  in  absence  of  ten- 
dency to  infiltration  and  in  absence  of  mitosis. 

Case  No.  4  (5755).  Adult  female. — The  tumor  was  situated 
beneath  the  skin  on  the  left  side  of  the  thorax.  It  was  soft,  lobu- 
lated, whitish  in  color  and  not  adherent  to  the  skin  or  surrounding 
tissues. 

Microscopically  this  growth  showed  a  more  pre-eminently 
adenomatous  structure  than  the  foregoing  tumors.  The  whole 
mass  was  generally  lobulated.  It  also  showed  a  beautiful  alveolar 
arrangement.  The  adenomatous  parts  were  divided  and  sub- 
divided into  large  and  small  masses  by  well  developed,  ripe  con- 
nective tissue.  The  alveoli  were  composed  chiefl}'  of  solid  masses 
of  cells,  with  only  occasional  evidence  of  lumens  which  were  filled 
with  inspissated  coagulated  proteid  material.  In  the  preceding 
tumors  the  cells  had  vesicular  nuclei,  and  a  homogeneous  granular 
protoplasm  that  frequently  showed  a  basophilic  tendency ;  in  this 
the  nuclei  were  small,  though  still  vesicular,  while  the  protoplasm 
was  spongy  and  clear.  There  was  no  evidence  of  reaction  on  the 
part  of  the  supporting  tissue ;  no  sign  of  infiltration  of  the  epi- 
thelial parts ;   no  evidence  of  rapid  growth  at  any  place. 

Case  No.  5  (16646).  Adult  female. — In  this  case  there  were 
two  tumors,  one  the  size  of  a  hen's  egg  under  the  skin  on  the  left 
side  of  the  thorax ;  one — a.  smaller  one — in  the  right  groin. 
Neither  was  adherent.  Both  showed  the  same  structure  as  the 
growth  in  Case  No.  5755. 

Case  No.  6  (5298).  Adult  female. — The  tumor  was  situated 
on  the  left  side  of  the  thorax  and  measured  5  x  2.5  x  2.5  centi- 
meters. It  was  hard,  cut  with  difficulty,  and  was  not  adherent., 
This  tum.or  was  an  example  of  fibro-adenoma  in  which  the  cell 
masses  showed,  as  a  general  rule,  central  lumens  surrounded  by 
but  a  single  row  of  cells.  The  whole  grcv/th  was  formed  of 
alveoli  each  of  which  was  divided  and  subdivided  into  small  acini 
by  a  scanty  fibrous  tissue.  The  gross  masses  were  limited  by  a 
well-formed — in  some  places  hyaline — connective  tissue.  The 
lumens  were  filled  with  coagulated  material.  There  was  no  evi- 
dence of  malignancy. 

Case  No.  7  (17142).  Adult  female. — The  animal  was  preg- 
nant.    In  the  right  inguinal  region  there  was  a  globular,  soft, 


316  DANDRIDGE  MEMORIAL 

lobulated,  vv-hile  tr.mor  measuring  about  2.5  centimeters  in  di- 
ameter. It  was  not  adherent.  The  tissue  of  this  growth  was 
composed  chietly  of  long,  free  and  interlacing  processes,  which 
were  constructed  of  a  narrow,  central,  vascular,  connective  tissue 
covered  with  from  one  to  several  layers  of  epithelial  cells. 
These  papillary  processes  originated  from  the  thin  hbrous  capsule 
that  surrounded  the  whole  mass.  In  this  capsule  a  few  eosino- 
philic cells  were  observed.     No  mitotic  figures  were  found. 

Remarks. — The  eight  tumors  described  in  the  preceding  para- 
graphs represent  growths  of  an  adenomatous  type,  the  variations 
within  the  group  being  determined  by  the  relative  development  of 
the  glandular  tissue  and  the  stroma.  In  all  but  one  case  (5)  the 
tumors  W'Cre  single.  In  the  one  case  tv.'o  similar  tumors  were 
present  in  different  parts  of  the  body.  All  the  animals  in  which 
the  sex  Was  recorded  were  females,  a  fact  that  indicates  the 
greater  tendency  of  females  in  rats,  as  in  human  beings,  to  ex- 
hibit mammary  growths.  This  sexual  difference  is  shown  in  Mc- 
Coy's figures  in  which  thirty  out  of  thirty-four  mammary  tumors 
v/ere  found  in  female  rats.  In  none  of  the  seven  animals  from 
which  these  growths  were  taken  was  there  any  evidence  of  a 
causative  factor. 

Case  No.  8  (6712).  Adult  female. — In  this  animal  a  slightly 
adherent,  soft  ovoid  tumor  the  size  of  a  hazel  nut  w^as  discovered 
in  the  right  inguinal  region,  and  upon  the  upper  lip  among  the 
large  whisker  hairs  was  a  small  epithelial  growth.  The  mass  in 
the  inguinal  region  proved  to  be  a  typical,  pure,  soft  fibroma.  The 
growth  on  the  lip  was  due  to  a  localized  hyperplasia  of  the  epi- 
thelium— a  hyperkeratosis — with  no  evidence  of  down  growth  and 
no  sign  of  malignant  change.  It  was  not  apparently  due  to  Sar- 
coptes  alepsis. 

Case  8  furnishes  the  only  example  of  a  pure  fibroma  in  our 
series.  In  McCoy's  series  there  were  sixteen  subcutaneous  fibro- 
mata. 

Case  No.  9  (13487).  Adult.  Sex? — The  tumor  in  this  case 
was  a  papilloma  of  the  bladder  associated  with  calculi.  The 
calculi  were  sent  to  Prof.  H.  B.  Ward  for  examination  for  ova 
of  parasitic  worms.  Up  to  the  present  time  no  ova  have  been 
demonstrated. 

The  growth  was  composed  of  elongated  branching  and  inter- 
lacing papillar}^  projections,  each  with  a  central  connective  tissue 
framework  carrying  blood  vessels,  and  covered  with  approxi- 
mately normal,  though  occasionally  hyperplastic,  epithelium.   The 


WOOLLEY    AXD    WHERRY  317 

spaces  between  the  interlacing  columns  were  sometimes  cystic, 
sometimes  completely  filled  with  cells  of  a  polygonal  squamous 
type,  but  without  evidence  of  keratinization.  In  such  cellular 
masses  the  central  cells  not  infrequently  showed  degenerative 
changes.     There  was  no  evidence  of  malignant  change. 

Interspersed  between  the  cells  at  various  places  in  the  growth 
were  ovoid  bodies  composed  of  a  central  round  protoplasmic 
mass  with  one  or  two  rounded  chromatin  masses.  These  central 
structures  were  surrounded  by  a  clear  space  limited  externally  by 
a  thin  sharply  demarcated  capsule.  These  structures  are  appar- 
ently the  result  of  retrogressive  metamorphosis  of  epithelial  cells, 
though  at  first  it  was  suggested,  because  of  the  fact  that  the  blad- 
der contained  calculi,  and  that  in  M.  norvegicus  bladder  worms 
(Trichosoma  Sp?)  were  not  infrequently  found,  that  they  might 
be  ova. 

Reinarks.^Case  Xo.  9  represents  the  only  example  of  bladder 
tumor  which  we  have  seen. 

Among  McCoy's  cases  there  was  no  example  of  such  a  tumor, 
which  indicates  that,  in  spite  of  the  frequency  of  bladder  worms 
and  calculi,  new  growths  of  the  bladder  are  very  uncommon. 

Case  Xo.  10.  Adult  female. — Above  the  labia  was  an  ulcer- 
ated surface  2.5  millimeters  in  diameter,  where  the  skin  was  thick- 
ened, hard,  and  ulcerated.  Attached  to  the  border  of  this  area 
was  a  nodular  mass  10x5x6  millimeters,  which  was  firm  in  con- 
sistence and  pinkish  on  section. 

The  labial  growth  showed  hyperplasia  of  the  epithelium  with 
distinct  invasion  of  the  subjacent  tissues.  The  surface  of  this 
hyperplastic  growth  was  ulcerated,  and  the  tumor  itself  was  infil- 
trated with  considerable  numbers  of  polymorphonuclear  leuco- 
cytes. The  epithelial  cells  in  the  invading  columns  shov^'ed  nu- 
merous mitotic  figures,  symmetrical  and  asymmetrical,  and  some 
epithelial  giant  cells. 

The  nodular  mass  connected  with  the  tumor  was  composed 
entirely  of  granulation  tissue. 

Remarks. — Epitheliomatous  growths  are  not  frequent  in  rats 
so  far  as  our  records  show,  and  in  ^McCoy's  series  there  is  no 
example. 

Borrel,  Gastinel  and  Gorescu^'  believe  that  acarids,  particu- 
larly Demodex  folliculorum,  play  an  important  role  in  the  pro- 
duction of  epitheliomas  in  man.  While  the  analog}'  is  not  com- 
plete, it  may  be  worth  mentioning  that  whereas  hyperkeratosis  of 
the  ears,  lips,  and  nose,  due  to  Sarcoptes  alepsis,  was  extremely 


318  D  A  NDRIDGE  MEMORIAL 

common  among  the  Norway  rats  on  the  Pacific  Coast,  yet  no 
tumors  were  found  at  these  sites. 

Case  No.  11  (8741).  Adult  female. — A  flattened  ovoid  tumor 
3  X  2.5  centimeters  was  found  in  the  right  groin.  It  was  not  ad- 
herent, w'as  readily  peeled  out,  was  soft  and  had  a  lobulated  ap- 
pearance. 

An  emulsion  of  this  tumor  was  made  in  physiological  saline 
and  injected  subcutaneously  into  a  small  white  rat.  No  growth 
of  parasitic  or  tumor  origin  appeared,  and  two  months  later  the 
rat  was  chloroformed  and  examined.  Nothing  abnormal  was 
discovered. 

The  bulk  of  the  tumor  was  composed  of  groups  of  cells  of 
squamous  epithelial  character  limited  by  a  well  developed,  par- 
tially hyaline,  connective  tissue.  The  minor  portion  was  a  gland- 
ular tissue  with  delicate  supporting  connective  tissue  structure. 
The  epithelial  islands  of  the  major  part  varied  in  size  and  shape. 
The  small  islands,  those  which  showed  for  the  most  part  little  or 
no  keratinization,  v/ere  generally  round.  The  larger  ones,  those 
fonned  of  an  external  zone  of  more  or  less  normal,  or  flattened 
epithelial  cells  and  a  central  area  of  cells  shov/ing  extreme  kera- 
tinization, or  merely  masses  of  keratohyalin,  were  polymorphous, 
lobulated,  trefoil-shaped,  or  round.  About  the  smaller  islands 
there  v/as  a  well  marked  small  round-cell  infiltration  with  occa- 
sional polymorphonuclear  leucocytes.  About  the  larger  there  was 
merely  a  well  formed  connective  tissue. 

In  many  instances  in  both  the  smaller  and  the  larger  islands 
the  epithelial  cell  boundaries  could  not  be  distinguished,  so  that 
the  central,  cellular  or  keratin  masses  seemed  to  be  surrounded  by 
a  more  or  less  complete  syncytial  layer.  In  various  places  the 
cells  contained  "inclusions,"  usually  acidophilic,  each  surrounded 
by  a  clear  achromatic  zone.  At  no  place  could  prickle  cells  be 
observed. 

The  glandular  portion  of  the  tumor  showed  longitudinal  and 
cross  sections  of  ducts  and  acini,  some  with  a  central  lumen;  some 
completely  filled  with  cells.  Among  the  typical  epithelial  cells 
were  others  that  had  a  yellow  granular  appearance,  the  result  of 
the  presence  in  the  protoplasm  of  numbers  of  flne  yellow  granules 
of  lipoid  (  ?). 

The  lining  epithelium  of  the  ducts  and  acini  were  composed  of 
one  or  several  layers  of  cells  of  cjdindrical  or  cuboid  form.  In 
the  supporting  tissue  there  was  very  little  evidence  of  reaction, 
except  for  occasional  basophilic  polymorphous  cells,  and  a  few 
eosinophiles.  No  mitotic  figures  v^-xre  found.  The  blood  vessels 
w^ere  slightly  congested. 

In  a  few  sections  small  colonies  or  clumps  of  organisms  were 


WOOLLEY    AND    WHERRY  319 

found.  The  individuals  of  these  colonies  were  rounded  or  spin- 
dle-shaped with  granular  and  vacuolated  bodies.  These  were 
arranged  tip  to  tip  in  chains  within  the  clumps.  Associated  with 
them  there  were  a  few  structures  resembling  mycelial  threads. 
The  identity  of  this  organism  which  was  found  only  in  the  aden- 
omatous part  of  the  tumor  cannot  be  more  than  guessed.  Its 
relation  to  the  tumor  can  only  be  conjectured. 

Remarks. — We  believe  that  there  are  but  four  similar  tum.ors 
on  record — one  reported  by  Tyzzer,  and  three  by  Murray ;  all  in 
mice.  These  tumors  are  interesting  examples  of  metaplasia  due 
most  likely  to  continued  irritation  of  one  sort  or  another,  and  are 
apparently  comparable  in  their  metaplastic  changes  to  the  inter- 
esting lung  tumors  described  by  Tyzzer  in  mice.  It  is  difficult, 
however,  to  discover  what  the  cause  of  the  irritation  w-as  in  our 
case.  There  were  microbic  parasites  present,  but  only  in  the 
purely  adenomatous  parts.  It  is  possible  that  the  absorbed  se- 
cretions from  these  organisms  was  responsible,  in  part,  for  the 
changes  in  the  tumor,  but  to  us  this  possibility  seems  remote. 

Case  Xo.  12  (10375).  Adult.  Sex?— This  rat  showed  a  soft 
tumor  the  size  of  a  filbert  in  the  submaxillary  region,  v»"hich  was 
adherent  to  an  adjacent  lymph  gland. 

Sections  showed  that  the  tumor  was  composed  of  small  poly- 
morphous cells  with  relatively  large  vesicular  nuclei  and  a  slightly- 
granular  protoplasm,  and  with  no  evidence  of  orderly  arrange- 
ment, except  that  they  are  more  compact!)^  related  to  the  blood 
vessels.  Mitotic  figures  were  nmnerous  and  in  some  instances 
asymmetrical.     It  was  a  small  polymorphous  cell  sarcoma. 

Case  Xo.  13  (9).  Adult  female. — This  rat  showed  a  large 
tumor  of  the  right  humerus,  ovoid  in  shape  and  measuring  4x3 
X  3  centimeters.  It  surrounded  the  upper  part  of  the  humerus 
and  involved  the  shoulder  joint.  It  was  soft  and  whitish  and 
apparentlv  very  vascular.  It  was  not  adherent  to  the  skin.  The 
humerus  itself  w-as  not  involved.  It  was  apparently  a  periosteal 
tumor. 

The  sections  shov/ed  a  partially  alveolar  structure  due  to  the 
peri-vascular  arrangement  of  the  tumor  cells  which  were  of  a 
short  spindle  shape  variety.  There  w^as  no  evidence  of  endo- 
thelial origin  of  the  tumor.  Occasional  giant  cells  w-ere  present. 
X^o  chondroblasts  w-ere  found.    Mitoses  were  frequent. 

Case  Xo.  14  (20804).  Adult  male. — The  animal  showed 
rather  marked  post-mortem  changes.     Just  above  and  attached 


320  DANDRIDGE   ME^IORIAL 

to  the  right  adrenal  was  a  soft  tumor  mass  the  size  of  a  small 
walnut.  It  was  smooth  and  glistening  and  the  surface  was  mot- 
tled with  reddish  white.  Between  it  and  the  stomach  were  similar 
smaller  nodules,  and  extending  anteriorly  across  the  abdominal 
cavity  was  a  large  lobulated  mass  3  x  2.5  x  1  centimeter  and  in 
the  mesentery  another  measuring  2x2x1.5  centimeters.  Be- 
neath the  liver  were  other  smaller  rounded  masses,  and  a  single 
one  in  the  left  kidney.  Throughout  the  liver  were  other  tumor 
growths,  and  the  peribronchial  lymph  glands  were  fused  together 
into  a  tumor-like  mass.  The  lungs  were  nodulated  and  on  section 
the  areas  of  consolidation  had  the  same  appearance  as  the  other 
tumor  masses. 

This  tumor  was  a  typical  lympho-sarcoma,  the  origin  of  which 
it  was  impossible  to  determine.  The  character  of  the  growths  in 
all  the  situations  was  identical. 

Case  No.  15  (7).  Adult.  Sex? — In  the  liver  region  a  tumor 
measuring  2x3  cubic  millimeters,  irregularly  ovoid,  and  appar- 
ently closely  associated  with  the  gall-bladder  was  found.  It  was 
adherent  to  the  edge  of  the  right  lobe  of  the  liver,  and  was  com- 
posed of  a  soft  grayish  or  whitish  tissue  with  areas  of  congestion. 
In  a  cleft  in  the  anterior  of  the  tumor  mass  was  a  free  Cysticercus 
fasciolaris.  The  vesicle  or  bladder  which  usually  encloses  the 
cysticercus  was  not  found.  A  cysticercus  within  its  cyst  was 
found  projecting  from  the  lower  border  of  the  right  lobe  of  the 
liver.    Part  of  the  tumor  was  fed  to  a  white  rat  with  no  result. 

The  tumor  proved  to  be  a  polymorphous  cell  sarcoma  com- 
posed of  round  and  spindle  cells,  with  numerous  giant  cells  scat- 
tered throughout.     INIitoses  were  frequent. 

Case  No.  16  (8).  Adult  female. — Attached  to  the  under  sur- 
face of  the  lower  lobe  of  the  liver  was  a  pinkish,  lobulated  tumor 
face  of  the  lower  lobe  of  the  liver  was  a  pinkish,  lobulated  tumor 
the  size  of  a  large  hen's  egg.  Throughout  the  omentum  and  mes- 
entery were  hundreds  of  metastatic  nodules  varying  in  size  from 
that  of  a  large  pea  to  0.5  millimeters  in  diameter.  As  in  the 
previous  case  free  cysticerci  fasciolaris  were  found  lying  in  smooth 
walled  channels  within  the  tumor  mass.  In  the  upper  part  of  the 
duodenum  was  a  small  ulcer  near  which  an  intestinal  worm  was 
attached.  In  the  non-secreting  portion  of  the  stomach  were  two 
small  crater-like  elevations  of  a  pale  color.  The  stomach  con- 
tained dipterous  larv?s  and  parasites  resembling  tricocephalus. 
The  intestine  contained  tapeworms.  In  the  cecum  were  some 
anchylostoma-Iike   worms. 

The  tumor  in  this  case  was  composed  of  polymorphous  and 
giant  cells  in  close  association  with  thousands  ,of  ova.  It 
had  apparently  originated  in  the  liver.     The  metastatic  nodules 


VV  O  O  L  L  E  Y     A  N  D     W  H  E  R  R  Y  321 

were  composed  of  cells  similar  to  those  of  the  primary  growth 
and  contained  no  ova. 

The  gastric  lesions  were  due  to  the  presence  of  small  sub- 
epithelial cystic  spaces  containing  ova  that  resemble  those  of  an- 
chylostoma.  About  these  there  is  no  evidence  of  malignant 
change. 

Case  No.  17  (22058).  Adult  female. — In  the  gastric  omen- 
tum there  was  a  large  lobulated  pinkish-white  tumor  the  size  of  a 
large  hen's  egg.  Scattered  throughout  the  mesentery  v/ere  simi- 
lar, but  smaller,  rounded  and  ovoid  nodules,  3-6-8  millimeters  in 
diameter.  Other  similar  masses  were  found  in  the  subperitoneal 
tissues.  Microscopic  study  showed  that  the  tumor  was  a  large 
spindle-cell  sarcoma  with  metastases  of  the  same  type.  Giant 
cells  were  present  in  small  numbers  and  mitoses  were  scanty. 

Case  No.  18  (4).  Adult  male. — In  the  abdomen  attached  to 
the  diaphragm  and  to  one  lobe  of  the  liver  was  a  tumor  mass, 
4  X  3x  3.5  centimeters,  irregularly  ovoid  in  shape  and  composed 
of  a  soft,  almost  fattv  tissue.  Attached  to  the  diaphragm  were 
three  or  four  smaller  nodules  two  to  six  millimeters  in  diameter ; 
tiattened,  rounded,  and  apparently  composed  of  the  same  sort  of 
tissue  as  the  larger  growth.  Cysticerci  were  present  in  the  liver 
substance  and  two  were  present  in  the  tumor.  The  tumor  was  a 
very  vascular  polymorphous  cell  sarcoma  and  occasionally  pre- 
sented a  p'crfect  pt-rivascular,  alveclar  api^earance.  There  were 
no  ova  present. 

Remarks. — This  group  of  cases  is  extremely  interesting  to  us 
for  the  reason  that  several  of  them  (15,  16,  and  18)  were  asso- 
ciated with  parasitic  worms,  and  because  several  of  them  (14,  16, 
17,  18)  produced  metastases. 

In  one  of  them  ( 16)  the  sarcomatous  changes  were  evidently 
associated  with  the  presence  of  an  enormous  number  of  ova. 
In  another  (17)  the  tumors  were  present  in  the  mesentery,  but 
in  the  absence  of  parasites  or  ova  outside  the  intestine.  In  still 
another  (16)  merely  cystic  spaces  were  present  in  the  stomach 
walls,  and  in  these  spaces  ova  of  another  sort  of  parasite  were 
present.  In  all  the  cases  directly  associated  with  the  presence  of 
immature  tapeworms,  cysticercus  fasciolaris.  the  malignant  tu- 
mors affected  the  liver.  These  facts  bring  up  the  questions 
whether  it  is  the  worms  themselves  or  their  excretions  that  are  to 
blame  for  the  tumor,  or  whether  it  is  the  ova  that  are  chiefly  to 
blame,  as  in  bilharziosis  of  the  bladder  and  intestine ;  whether  the 
tenia?  alone,  either  through  their  presence  and  secretion  and  ova 


2il2  DAN  BRIDGE  iM  E  M  O  R  I  A  L 

are  active  in  producing  these  tumors ;  and  whether  the  liver  is 
more  prone  to  undergo  malignant  change  as  the  result  of  these 
various  influences.  Saul  did  some  implantation  experiments 
using  various  portions  of  the  cysticercus  fasciolaris.  Rats  inocu- 
lated with  the  head  end  and  middle  portions  died  of  evident  tox- 
emia. One  inoculated  with  the  tail  end  developed  a  fibro-sarcoma 
at  the  site  of  implantation.  Reimplantation  with  a  portion  of  his 
tumor  resulted  in  infection. 

It  is  interesting  that  so  many  tumors  of  rats  are  associated 
with  parasitic  worms.  In  twelve  of  McCoy's  cases  parasites  were 
associated  with  tumors.  One  of  these  growths  was  a  fibroma. 
The  other  eleven  were  sarcomas.    All  were  of  hepatic  origin. 

Case  No.  19  (8994).  Adult.  Sex?— All  of  the  left  kidney 
except  the  upper  pole  was  replaced  by  a  tumor  mass,  ovai  \\\ 
form,  the  size  of  a  hen's  egg,  smooth,  and  encapsulated.  On  sec- 
tion it  appeared  partially  fatty  and  necrotic,  partially  hemor- 
rhagic. The  tumor  mass  appeared  on  microscopic  examination  to 
be  composed  of  three  parts;  one  a  mass  of  recent  hemorrhage; 
one  a  laminated  mass  of  partially  organized  clotted  blood ;  one 
the  larger  part  composed  of  renal  and  tumor  tissue.  The  kidney 
substance  itself  showed  cloudy  swelling,  edema,  and  interstitial 
accumulation  of  small,  round  cells.  The  interstitial  changes  were 
more  marked  in  the  immediate  vicinity  of  the  tumor  mass,  and  in 
this  region  there  were  also  occasional  giant  cells  of  renal  epithelial 
origin.  Though  the  tumor  itself  was  as  a  rule  well  demarcated 
from  the  kidney  substance,  there  were  points  at  which  an  ap- 
parent transition  could  be  made  out,  so  that  it  seemed  evident  that 
the  papillo-adenomatous  tumor  mass  was  of  renal  origin.  In  oc- 
casional spots  there  seemed  to  be  some  evidence  of  malignant  re- 
version in  the  connective  tissue. 

Case  No.  20  (3)  Adult  male. — In  this  animal  the  central  part 
of  one  of  the  kidneys  was  occupied  by  a  grayish-yellow  and 
pinkish-white  mass  which  was  bounded  by  approximately  normal 
renal  tissue. 

Microscopically  this  tumor  resembled  the  preceding  one.  There 
was  less  hemorrhage  in  the  tumor,  and  more  evidence  of  chronic 
interstitial  changes  in  the  kidney  substance.  The  tumor  showed 
adenomatous,  cystic  and  intracystic  arrangement,  with  transition 
from  renal  substance  to  tumor.  There  was  also  some  evidence 
of  sarcomatous  change  in  areas  where  the  cells  had  a  localized 
tendency  to  assume  a  spindle  form,  especially  in  those  parts  of  the 
tumor  where,  with  a  rich  vascular  supply,  the  cells  had  a  more  or 
less  perfect  radial  perivascular  arrangement. 


WOOLLEY    AND    WHERRY 


323 


Case  No.  21  (5).  Adult  female. — The  organs  seemed  generally 
healthy  except  the  left  kidney,  which  was  enlarged,  and  in  its  an- 
terior had  had  a  wdiitish  appearance.  The  left  adrenal  was  imme- 
diately in  juxtaposition  with  the  tumor  area  but  separate  from  it. 

The  tumor  was  composed  of  cells  smaller  than  those  of  the 
two  preceding  cases,  of  a  more  solid  type  and  with  fewer  giant 
cells.  Within  the  tumor  itself  were  well-preserved  glomeruli  which 
had  been  surrounded  in  the  progressive  growth  of  the  neoplasm. 
In  this  case  as  in  the  others  there  was  evidence  of  renal  origin  in 
the  gradual  transition  of  renal  cells  at  the  tumor  borders. 

Remarks. — In  spite  of  certain  likenesses  to  adrenal  tissue  we 
believe  that  these  tumors  have  originated  in  renal  tissue  and 
not  in  misplaced  adrenal  rests;  that  they  are  malignant  renal 
adenomas,  therefore,  and  not  hypernephromas,  in  the  sense  of 
Grawitz.  This  seems  reasonable  because  of  the  evidences  of 
malignant  transformation  in  the  cells  immediately  about  the  tumor 
proper.  We  realize  that  this  transformation  may  be  explained 
as  being  the  effect  of  the  presence  of  the  tumor  rather  than  the 
cause  of  it,  but  w^e  think  that  there  are  greater  similarities  between 
the  kidney  proper  and  the  tumors  than  between  adrenal  tissue  and 
the  tumors. 

In  McCoy's  series  of  eleven  renal  tumors,  one  produced  meta- 
stasis.   Of  our  cases  none  metastasized. 


SUMMARY. 

Total  rats  examined. 

23,000 

Total  rats  with  tumiors, 

21 

Total  tumors. 

22 

Total  epithelial  tumors. 

14 

63.64% 

Total  connective  tissue. 

8 

36.36% 

Tumors  oJ 

breast, 

Q 

40.9  7o 

(<              a 

kidney, 

3 

13.64% 

a              (I 

bladder, 

4.54% 

a              li 

skin. 

4.54% 

ti              << 

connective  tissue, 

4.54% 

a               a 

liver, 

3 

13.64% 

a              .< 

mesentery. 

4.54% 

t(              a 

submaxillary  gland. 

4.54% 

a               •< 

periosteum, 

4.54% 

a               ii 

lymph  glands. 

4.54% 

Malignant, 

11 

50.50% 

Metastasis, 

4 

18.18% 

Associated  with 

parasites. 

3 

13.64% 

324  DA  NDRIDGE  MEMORIAL 


BIBLIOGRAPHY. 

McCoy :  The  Rat  in  Its  Relation  to  Public  Health.    Public  Health  and 
Marine  Hospital  Service,  Washington,  1910,  64. 

Wherry,  Walker  and  Howell:  Journal  A.  M.  A.,  1908,  1.  1165. 
Borrel,  Gestinel  and  Gorescu :  Ann.  d.  I'lnst.  Past,  1909,  xxiii,  97. 
Saul :  Centr.  f.  Bakt.,  I.  Abth.  Orig.,  1908,  xlvii,  444. 


A  COMPUTING  CHART  FOR  MAKING  A  DIFFEREN- 
TIAL LEUCOCYTE  COUNT.* 


BY  A.    E.  OSMOND^    M.D. 

Any  laboratory  worker  who  has  had  any  amount  of  blood  work 
to  do,  especially  in  making  differential  leucocyte  counts,  has  been 
more  or  less  troubled  with  the  necessity  of  having  to  figure  out 
the  percentages  of  the  various  types  of  cells  and  the  liability  of 
error. 


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tory of  the  Cincinnati  Hospital,  and  we  have  found  it  quite 
convenient  in  simplifying  the  work  and  removing  sources  of  error. 
The  chart  is  inexpensive  and  can  be  made  out  of  a  piece  of  ground 
glass  or  a  slate,  suitably  ruled  and  marked  in  ink  so  as  to  be 

*  Reprinted  from  the  Journal  of  the  American  Medical  Association, 
January  8,  1910,  Vol.  LIV,  p.  124. 

325 


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OSMOND  327 

permanent.  The  temporary  markings  are  made  in  pencil,  can  be 
readily  erased,  and  the  chart  is  again  ready  for  service. 

It  is  figured  out  on  a  basis  of  a  count  of  two  hundred  leucocytes, 
and  marked  on  the  left  to  designate  the  various  types  of  cells,  as 
polymorphonuclear,  large  lymphocytes,  small  lymphocytes,  eosino- 
philes,  transitional  cells,  etc.  At  the  bottom  are  the  calculated 
(percentages,  and  at  the  top  the  actual  number  of  cells  counted 
when  the  vertical  columns  are  filled. 

The  heavy  lines  running  vertically  are  put  in  simply  to  facilitate 
the  count,  by  indicating  when  fifty,  one  hundred  or  one  hundred 
and  fifty  units  are  counted  for  a  certain  type  of  cell,  and  by  re- 
ferring to  the  figures  in  the  top  row  one  can  at  once  read  off  the 
actual  number  of  each  type  of  cell  counted,  and  easily  sum  up 
when  a  total  of  two  hundred  has  been  reached. 

This  being  done,  the  percentages  are  read  ofif  directly  from  the 
bottom  figures  and  the  usual  calculating  with  the  possibility  of 
error  is  entirely  removed. 


THE  CINCINNATI  RESEARCH  SOCIETY. 


Recognizing  general  science  as  the  basis  of  medicine  and  realiz- 
ing the  value  of  mutual  aid  in  researches  along  this  line,  there 
was  felt  a  need  in  Cincinnati  of  an  organization  affording  these 
advantages. 

On  Thursday,  January  28,  1897,  the  following  physicians — 
Drs.  Jos.  Eichberg,  F.  W.  Langdon,  E.  W.  Mitchell,  W.  E. 
Schenck,  H.  Freudenberg,  P.  M.  Ashburn,  A.  H.  Freiberg,  E  H. 
Shields,  T.  O.  Edwards,  S.  Rothenberg,  H.  W.  Bettmann  and 
S.  P.  Kramer — met  in  the  office  of  the  last  named  and  formally 
organized  the  Society  for  Medical  Research.  Letters  of  approval 
were  received  from  a  number  of  other  physicians  of  the  city. 
The  society  was  organized  along  lines  similar  to  The  Research 
Club  of  London,  and  the  work  of  the  society  was  intended  to 
embrace  the  scientific  side  of  medicine  as  embodied  in  gross  and 
microscopic  anatomy  and  pathology,  bacteriology,  physiology, 
physics  and  biology.  The  society  was  in  no  way  to  conflict  with 
the  work  of  the  Academy,  but  should  devote  itself  exclusively 
to  demonstrations  of  original  research.  Dr.  Kramer  was  elected 
president,  and  Dr.  Bettmann  secretary  and  treasurer. 

Since  its  inception  the  society  has  enjoyed  a  most  successful 
career,  and  is,  in  all  probability,  one  of  the  most  representative 
medical  bodies  in  Cincinnati  today. 

The  meetings,  the  first  Thursday  of  each  month  at  the  Cin- 
cinnati Hospital  Laboratory,  are  regularly  attended,  and  the  in- 
terest in  the  proceedings  has  been  sufficiently  active  to  render  the 
discussion  on  every  occasion  keen,  highly  instructive  and  of  great 
scientific  value. 

On  February  2,  1911,  the  name  of  the  society  was  changed 
to  the  Cincinnati  Research  Society,  in  so  far  as  quite  a  number 
of  papers  are  presented  from  time  to  time  by  scientific  men,  who 
are  not  physicians,  but  who  are  nevertheless  eligible  to  member- 
ship in  the  societ)\ 

329 


330  DANDRIDGE  MEMORIAL 

The  officers  of  the  society  are : 

President — Dr.  Martin  H.  Fischer. 

Vice-President — Dr.  Samuel  Iglauer. 

Secretary  and  Treasurer — Dr.  J.  L.  Tuechter. 

Executive  Committee — Dr.  John  Greiwe,  Dr.  S.  P.  Kramer. 

Beginning  in  Jpnuary,  1912,  the  meetings  of  the  society  have 
been  held  in  the  Ohio-Miami  Medical  College  building.  This 
move  was  made  necessary  by  the  largely  increased  attendance. 


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